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image of Pyrimidine: A Privileged Scaffold for the Development of Anticancer Agents as Protein Kinase Inhibitors (Recent Update)

Abstract

The pyrimidine nucleus is a fundamental component of human DNA and RNA, as well as the backbone of many therapeutic agents. Its significance in medicinal chemistry is well-established, with pyrimidine derivatives receiving considerable attention due to their potent anticancer properties across various cancer cell lines. Numerous derivatives have been synthesized, drawing structural inspiration from known anticancer agents like dihydropyrimidine compounds, which include the active cores of drugs such as

5-fluorouracil and monastrol, both of which have demonstrated strong anticancer efficacy. Additionally, various pyrimidine derivatives have been developed through different synthetic pathways, exhibiting promising anticancer potential. In response to the growing need for effective cancer treatments, recent efforts have focused on synthesizing and exploring novel pyrimidine derivatives with improved efficacy and specificity. This review aims to highlight the versatility of pyrimidine-based compounds in cancer therapy, emphasizing not only their potency and binding affinity but also their optimal interaction with diverse biological targets. The goal is to facilitate the design of new pyrimidine derivatives with enhanced anticancer potential, providing effective solutions for the treatment of various cancer types.

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2025-01-03
2025-01-30
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References

  1. Rumgay H. Shield K. Charvat H. Ferrari P. Sornpaisarn B. Obot I. Islami F. Lemmens V.E.P.P. Rehm J. Soerjomataram I. Global burden of cancer in 2020 attributable to alcohol consumption: a population-based study. Lancet Oncol. 2021 22 8 1071 1080 10.1016/S1470‑2045(21)00279‑5 34270924
    [Google Scholar]
  2. Ballerini P. Contursi A. Bruno A. Mucci M. Tacconelli S. Patrignani P. Inflammation and Cancer: From the Development of Personalized Indicators to Novel Therapeutic Strategies. Front. Pharmacol. 2022 13 838079 838096 10.3389/fphar.2022.838079 35308229
    [Google Scholar]
  3. Hibino S. Kawazoe T. Kasahara H. Itoh S. Ishimoto T. Sakata-Yanagimoto M. Taniguchi K. Inflammation-Induced Tumorigenesis and Metastasis. Int. J. Mol. Sci. 2021 22 11 5421 5458 10.3390/ijms22115421 34063828
    [Google Scholar]
  4. Tang Y.Y. Wang D.C. Wang Y.Q. Huang A.F. Xu W.D. Emerging role of hypoxia-inducible factor-1α in inflammatory autoimmune diseases: A comprehensive review. Front. Immunol. 2023 13 1073971 1073986 10.3389/fimmu.2022.1073971 36761171
    [Google Scholar]
  5. Dvornikova K.A. Platonova O.N. Bystrova E.Y. Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways. Int. J. Mol. Sci. 2023 24 3 2425 2447 10.3390/ijms24032425 36768744
    [Google Scholar]
  6. Witte C.P. Herde M. Nucleotide Metabolism in Plants. Plant Physiol. 2020 182 1 63 78 10.1104/pp.19.00955 31641078
    [Google Scholar]
  7. Yadav M. Kumar R. Krishnamurthy R. Chemistry of Abiotic Nucleotide Synthesis. Chem. Rev. 2020 120 11 4766 4805 10.1021/acs.chemrev.9b00546 31916751
    [Google Scholar]
  8. Alavala R.R. Kulandaivelu U. Bonagiri P. Boyapati S. Jayaprakash V. Subramaniam A.T. Synthesis and Antiviral Activity of Dihydropyrimidines - Ciprofloxacin Mannich bases Against Various Viral Strains. Antiinfect. Agents 2015 13 154 165 10.2174/221135251302151029111113
    [Google Scholar]
  9. Boyer Z.W. Kessler H. Brosman H. Ruud K.J. Falkowski A.F. Viollet C. Bourne C.R. O’Reilly M.C. Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure–Activity Relationships and Mechanism of Action. ACS Omega 2022 7 42 37907 37916 10.1021/acsomega.2c05071 36312355
    [Google Scholar]
  10. Ishwar Bhat K. Kumar A. Thara P.V. Kumar P. Synthesis, characterization and biological activity studies of some substituted pyrimidine derivatives. Indian J. Heterocycl. Chem. 2014 4 271 276 10.1044/1980‑iajpr.14369
    [Google Scholar]
  11. El-Malah A. Mahmoud Z. Hamed Salem H. Abdou A.M. Soliman M.M.H. Hassan R.A. Design, ecofriendly synthesis, anticancer and antimicrobial screening of innovative Biginelli dihydropyrimidines using β-aroylpyruvates as synthons. Green Chem. Lett. Rev. 2021 14 2 221 233 10.1080/17518253.2021.1896789
    [Google Scholar]
  12. Huang J.X. Hou K.Q. Hu Q.L. Chen X.P. Li J. Chan A.S.C. Xiong X.F. Organocatalytic Asymmetric Three-Component Povarov Reactions of Anilines and Aldehydes. Org. Lett. 2020 22 5 1858 1862 10.1021/acs.orglett.0c00206 32083880
    [Google Scholar]
  13. Jacobson K. Costanzi S. Ohno M. Joshi B. Besada P. Xu B. Tchilibon S. Molecular recognition at purine and pyrimidine nucleotide (P2) receptors. Curr. Top. Med. Chem. 2004 4 8 805 819 10.2174/1568026043450961 15078212
    [Google Scholar]
  14. Zhong L. Li Y. Xiong L. Wang W. Wu M. Yuan T. Yang W. Tian C. Miao Z. Wang T. Yang S. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct. Target. Ther. 2021 6 1 201 10.1038/s41392‑021‑00572‑w 34054126
    [Google Scholar]
  15. Elkaeed E.B. El Salam H.A.A. Sabt A. Al-Ansary G.H. Eldehna W.M. Recent advancements in the development of anti-breast cancer synthetic small molecules. Molecules 2021 26 7611 10.3390/molecules26247611
    [Google Scholar]
  16. Mollick T. Laín S. Modulating pyrimidine ribonucleotide levels for the treatment of cancer. Cancer Metab. 2020 8 1 12 10.1186/s40170‑020‑00218‑5 33020720
    [Google Scholar]
  17. Siegel R.L. Miller K.D. Fuchs H.E. Jemal A. Cancer statistics, 2022. CA Cancer J. Clin. 2022 72 1 7 33 10.3322/caac.21708 35020204
    [Google Scholar]
  18. Dhingra K. Industry corner: Early drug development. Ann. Oncol. 2016 27 1161 1164 10.1093/annonc/mdw140 27045101
    [Google Scholar]
  19. Bedi S. Khan S.A. AbuKhader M.M. Alam P. Siddiqui N.A. Husain A. A comprehensive review on Brigatinib – A wonder drug for targeted cancer therapy in non-small cell lung cancer. Saudi Pharm. J. 2018 26 6 755 763 10.1016/j.jsps.2018.04.010 30202213
    [Google Scholar]
  20. Irfan R. Mousavi S. Alazmi M. Saleem R.S.Z. A Comprehensive Review of Aminochalcones. Molecules 2020 25 22 5381 10.3390/molecules25225381 33213087
    [Google Scholar]
  21. Elrefay M. Elfiky A. Sayed R. Zaki H. Snake venom, bee venom and their components exert an anti-cancer effect by triggering apoptosis and cell cycle arrest in prostate cancer. Bull. Fac. Pharm. Cairo Univ. 2019 57 2 148 156 10.21608/bfpc.2019.101875
    [Google Scholar]
  22. Sarkar N. Singh A. Kumar P. Kaushik M. Protein kinases: Role of their dysregulation in carcinogenesis, identification and inhibition. Drug Res. (Stuttg.) 2023 73 4 189 199 10.1055/a‑1989‑1856 36822216
    [Google Scholar]
  23. Ubersax J.A. Ferrell J.E. Jr Mechanisms of specificity in protein phosphorylation. Nat. Rev. Mol. Cell Biol. 2007 8 7 530 541 10.1038/nrm2203 17585314
    [Google Scholar]
  24. Turdo A. D’Accardo C. Glaviano A. Porcelli G. Colarossi C. Colarossi L. Mare M. Faldetta N. Modica C. Pistone G. Bongiorno M.R. Todaro M. Stassi G. Targeting Phosphatases and Kinases: How to Checkmate Cancer. Front. Cell Dev. Biol. 2021 9 690306 10.3389/fcell.2021.690306 34778245
    [Google Scholar]
  25. An E. Brognard J. Orange is the new black: Kinases are the new master regulators of tumor suppression. IUBMB Life 2019 71 6 738 748 10.1002/iub.1981 30548122
    [Google Scholar]
  26. Pan L. Li J. Xu Q. Gao Z. Yang M. Wu X. Li X. HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review. Medicine (Baltimore) 2024 103 24 e38508 10.1097/MD.0000000000038508 38875362
    [Google Scholar]
  27. Sever R. Brugge J.S. Genetic and epigenetic mechanisms of cancer progression. Cold Spring Harb. Perspect. Med. 2015 5 a006098 10.1101/cshperspect.a006098 25833940
    [Google Scholar]
  28. Delou J.M.A. Souza A.S.O. Souza L.C.M. Borges H.L. Highlights in Resistance Mechanism Pathways for Combination Therapy. Cells 2019 8 9 1013 1042 10.3390/cells8091013 31480389
    [Google Scholar]
  29. Ardito F. Giuliani M. Perrone D. Troiano G. Muzio L.L. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int. J. Mol. Med. 2017 40 2 271 280 10.3892/ijmm.2017.3036 28656226
    [Google Scholar]
  30. Force T. Kuida K. Namchuk M. Parang K. Kyriakis J.M. Inhibitors of protein kinase signaling pathways: emerging therapies for cardiovascular disease. Circulation 2004 109 10 1196 1205 10.1161/01.CIR.0000118538.21306.A9 15023894
    [Google Scholar]
  31. Masbuchin A.N. Widodo M.S. Rohman M.S. Liu P.Y. The two facets of receptor tyrosine kinase in cardiovascular calcification—can tyrosine kinase inhibitors benefit cardiovascular system? Front. Cardiovasc. Med. 2022 9 986570 10.3389/fcvm.2022.986570 36237897
    [Google Scholar]
  32. Mahmoud M.E. Ahmed E.M. Ragab H.M. Eltelbany R.F.A. Hassan R.A. Design, synthesis, biological evaluation, and docking studies of novel triazolo[4,3- b ]pyridazine derivatives as dual c-Met/Pim-1 potential inhibitors with antitumor activity. RSC Advances 2024 14 41 30346 30363 10.1039/D4RA04036H 39318461
    [Google Scholar]
  33. Vijayan R. Baby B. Antony P. Al Halabi W. Al Homedi Z. Structural insights into the polypharmacological activity of quercetin on serine/threonine kinases. Drug Des. Devel. Ther. 2016 10 3109 3123 10.2147/DDDT.S118423 27729770
    [Google Scholar]
  34. Correa-Sáez A. Jiménez-Izquierdo R. Garrido-Rodríguez M. Morrugares R. Muñoz E. Calzado M.A. Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases. Cell. Mol. Life Sci. 2020 77 23 4747 4763 10.1007/s00018‑020‑03556‑1 32462403
    [Google Scholar]
  35. Yoshida S. Yoshida K. New insights into the roles for DYRK family in mammalian development and congenital diseases. Genes Dis. 2023 10 3 758 770 10.1016/j.gendis.2021.12.004 37396550
    [Google Scholar]
  36. Wolanin P.M. Thomason P.A. Stock J.B. Histidine protein kinases: key signal transducers outside the animal kingdom. Genome Biol. 2002 3 10 reviews3013.1 10.1186/gb‑2002‑3‑10‑reviews3013 12372152
    [Google Scholar]
  37. de Claro R.A. McGinn K.M. Verdun N. Lee S.L. Chiu H.J. Saber H. Brower M.E. Chang C.J.G. Pfuma E. Habtemariam B. Bullock J. Wang Y. Nie L. Chen X.H. Lu D.R. Al-Hakim A. Kane R.C. Kaminskas E. Justice R. Farrell A.T. Pazdur R. FDA approval: Ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin. Cancer Res. 2015 21 16 3586 3590 10.1158/1078‑0432.CCR‑14‑2225 26275952
    [Google Scholar]
  38. Alu A. Lei H. Han X. Wei Y. Wei X. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies. J. Hematol. Oncol. 2022 15 1 138 173 10.1186/s13045‑022‑01353‑w 36183125
    [Google Scholar]
  39. Dailah H.G. Hommdi A.A. Koriri M.D. Algathlan E.M. Mohan S. Potential role of immunotherapy and targeted therapy in the treatment of cancer: A contemporary nursing practice. Heliyon 2024 10 2 e24559 10.1016/j.heliyon.2024.e24559 38298714
    [Google Scholar]
  40. Liauw J. Brunault R. Quesenberry M. Bakow B. Split and reduced-dose imatinib in chronic myeloid leukemia: Case report. JHOP 2024 14 3 121 123
    [Google Scholar]
  41. Iqbal N. Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother. Res. Pract. 2014 2014 1 9 10.1155/2014/357027 24963404
    [Google Scholar]
  42. Uzer E. Ünal A. Yavuz Köker M. Ali Doğan S. The side effects of imatinib. Turk. J. Haematol. 2013 30 3 341 341 10.4274/TJH‑2011.0018 24385822
    [Google Scholar]
  43. Hazarika M. Jiang X. Liu Q. Lee S.L. Ramchandani R. Garnett C. Orr M.S. Sridhara R. Booth B. Leighton J.K. Timmer W. Harapanhalli R. Dagher R. Justice R. Pazdur R. Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin. Cancer Res. 2008 14 17 5325 5331 10.1158/1078‑0432.CCR‑08‑0308 18765523
    [Google Scholar]
  44. Jabbour E. Kantarjian H. Cortes J. Jabbour E. Development and targeted use of nilotinib in chronic myeloid leukemia. Drug Des. Devel. Ther. 2008 2 233 243 10.2147/DDDT.S3181 19920910
    [Google Scholar]
  45. Weisberg E. Manley P. Mestan J. Cowan-Jacob S. Ray A. Griffin J.D. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br. J. Cancer 2006 94 12 1765 1769 10.1038/sj.bjc.6603170 16721371
    [Google Scholar]
  46. Wasekar N. Mohite A. S C. P V. P R. B S. Jijina F. Nilotinib induced skin rash in chronic myeloid leukemia patients: A case series. Int. J. Med. Sci. Public Health 2017 6 3 1 10.5455/ijmsph.2017.1058601112016
    [Google Scholar]
  47. Deisseroth A. Kaminskas E. Grillo J. Chen W. Saber H. Lu H.L. Rothmann M.D. Brar S. Wang J. Garnett C. Bullock J. Burke L.B. Rahman A. Sridhara R. Farrell A. Pazdur R. Food U.S. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin. Cancer Res. 2012 18 12 3212 3217 10.1158/1078‑0432.CCR‑12‑0653 22544377
    [Google Scholar]
  48. Ostojic A. Vrhovac R. Verstovsek S. Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011 7 9 1035 1043 10.2217/fon.11.81 21919691
    [Google Scholar]
  49. Furia F. Canevini M.P. Federici A.B. Carraro M.C. Unexpected neurological symptoms of ruxolitinib: A case report. J. Hematol. 2020 9 4 137 139
    [Google Scholar]
  50. FDA fast track designation for narmafotinib in advanced pancreatic cancer. 2024 Available from: https://www.prnewswire.com/news-releases/fda-fast-track-designation-for-narmafotinib-in-advanced-pancreatic-cancer-302253755.html(accessed on 23-10-2024)
  51. Tagrisso (osimertinib) receives US FDA full approval. 2017 Available from: https://www.astrazeneca.com/media-centre/press-releases/2017/tagrisso-osimertinib-receives-us-fda-full-approval-31032017.html#!(accessed on 23-10-2024)
  52. Liam C.K. Osimertinib as first-line treatment of EGFR mutant advanced non-small-cell lung cancer. Transl. Lung Cancer Res. 2017 6 S1 Suppl. 1 S62 S66 10.21037/tlcr.2017.10.10 29299414
    [Google Scholar]
  53. Gomatou G. Syrigos N. Kotteas E. Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options. Cancers (Basel) 2023 15 3 841 861 10.3390/cancers15030841 36765799
    [Google Scholar]
  54. Shalata W. Abu Jama A. Dudnik Y. Abu Saleh O. Shalata S. Tourkey L. Sheva K. Meirovitz A. Yakobson A. Adverse Events in Osimertinib Treatment for EGFR-Mutated Non-Small-Cell Lung Cancer: Unveiling Rare Life-Threatening Myelosuppression. Medicina (Kaunas) 2024 60 8 1270 1279 10.3390/medicina60081270 39202551
    [Google Scholar]
  55. Kelley R.K. Erlotinib in the treatment of advanced pancreatic cancer. Biologics 2008 2 1 83 95 10.2147/btt.s1832
    [Google Scholar]
  56. Ling Y.H. Li T. Yuan Z. Haigentz M. Weber T.K. Perez-Soler R. Re: Ling Y-H, Li T, Yuan Z, Haigentz M, Jr., Weber TK, and Perez-Soler R (2007) Erlotinib, an Effective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces p27 KIP1 Up-Regulation and Nuclear Translocation in Association with Cell Growth Inhibition and G 1 /S Phase Arrest in Human Non-Small-Cell Lung Cancer Cell Lines. Mol Pharmacol 72:248–258; doi:10.1124/mol.107.034827. Mol. Pharmacol. 2015 88 2 390 10.1124/mol.115.08er15a
    [Google Scholar]
  57. Becker A. van Wijk A. Smit E.F. Postmus P.E. History C. Side-effects of long-term administration of erlotinib in patients with non-small cell lung cancer. J. Thorac. Oncol. 2010 5 9 1477 1480 10.1097/JTO.0b013e3181e981d9 20736807
    [Google Scholar]
  58. Ryan Q. Ibrahim A. Cohen M.H. Johnson J. Ko C. Sridhara R. Justice R. Pazdur R. FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist 2008 13 10 1114 1119 10.1634/theoncologist.2008‑0816 18849320
    [Google Scholar]
  59. Cadena García J.M. Giraldo Murillo C.E. Ramos Jaramillo M. EGFR and HER2 small molecules inhibitors as potential therapeutics in veterinary oncology. Revista Colombiana de Ciencias Químico-Farmacéuticas 2020 49 2 452 471 10.15446/rcciquifa.v49n2.89898
    [Google Scholar]
  60. Chan A. Lapatinib - overview and current role in metastatic breast cancer. Cancer Res. Treat. 2006 38 4 198 200 10.4143/crt.2006.38.4.198 19771242
    [Google Scholar]
  61. Sang Y.B. Kim J.H. Kim C.G. Hong M.H. Kim H.R. Cho B.C. Lim S.M. The Development of AXL Inhibitors in Lung Cancer: Recent Progress and Challenges. Front. Oncol. 2022 12 811247 811257 10.3389/fonc.2022.811247 35311091
    [Google Scholar]
  62. Chen F. Song Q. Yu Q. Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. Am. J. Cancer Res. 2018 8 8 1466 1482 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6129480 30210917
    [Google Scholar]
  63. Cella D. Beaumont J.L. Pazopanib in the treatment of advanced renal cell carcinoma. Ther. Adv. Urol. 2016 8 1 61 69 10.1177/1756287215614236 26834841
    [Google Scholar]
  64. Kasper B. Hohenberger P. Pazopanib: a promising new agent in the treatment of soft tissue sarcomas. Future Oncol. 2011 7 12 1373 1383 10.2217/fon.11.116 22112314
    [Google Scholar]
  65. Que Y. Liang Y. Zhao J. Ding Y. Peng R. Guan Y. Zhang X. Treatment-related adverse effects with pazopanib, sorafenib and sunitinib in patients with advanced soft tissue sarcoma: a pooled analysis. Cancer Manag. Res. 2018 10 2141 2150 10.2147/CMAR.S164535 30050324
    [Google Scholar]
  66. Linghu X. Wong N. Blake J.F. Gaudino J.J. Moffat J.G. 2018 10.1021/bk‑2018‑1307.ch001
  67. Yang M. Sun S. Lv H. Wang W. Li H. Sun J. Zhang Z. RETRACTED: Ravoxertinib Improves Long-Term Neurologic Deficits after Experimental Subarachnoid Hemorrhage through Early Inhibition of Erk1/2. ACS Omega 2023 8 22 19692 19704 10.1021/acsomega.3c01296 37305289
    [Google Scholar]
  68. Benson C. White J. Bono J.D. O’Donnell A. Raynaud F. Cruickshank C. McGrath H. Walton M. Workman P. Kaye S. Cassidy J. Gianella-Borradori A. Judson I. Twelves C. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br. J. Cancer 2007 96 1 29 37 10.1038/sj.bjc.6603509 17179992
    [Google Scholar]
  69. Meijer L. Raymond E. From Starfish Oocytes to Clinical Trials Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc. Chem. Res. 2003 36 6 417 425 10.1021/ar0201198 12809528
    [Google Scholar]
  70. Jackson R.C. Barnett A.L. McClue S.J. Green S.R. Seliciclib, a cell-cycle modulator that acts through the inhibition of cyclin-dependent kinases. Expert Opin. Drug Discov. 2008 3 1 131 143 10.1517/17460441.3.1.131 23480144
    [Google Scholar]
  71. Pang K. Wang W. Qin J.X. Shi Z.D. Hao L. Ma Y.Y. Xu H. Wu Z.X. Pan D. Chen Z.S. Han C.H. Role of protein phosphorylation in cell signaling, disease, and the intervention therapy. MedComm 2022 3 4 e175 10.1002/mco2.175 36349142
    [Google Scholar]
  72. Dai X.J. Xue L.P. Ji S.K. Zhou Y. Gao Y. Zheng Y.C. Liu H.M. Liu H.M. Triazole-fused pyrimidines in target-based anticancer drug discovery. Eur. J. Med. Chem. 2023 249 115101 10.1016/j.ejmech.2023.115101 36724635
    [Google Scholar]
  73. K Bhanumathy K. Balagopal A. Vizeacoumar F.S. Vizeacoumar F.J. Freywald A. Giambra V. Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia. Cancers (Basel) 2021 13 2 184 204 10.3390/cancers13020184 33430292
    [Google Scholar]
  74. Kim M. Baek M. Kim D.J. Protein Tyrosine Signaling and its Potential Therapeutic Implications in Carcinogenesis. Curr. Pharm. Des. 2017 23 29 4226 4246 10.2174/1381612823666170616082125 28625132
    [Google Scholar]
  75. Yamaoka T. Kusumoto S. Ando K. Ohba M. Ohmori T. Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int. J. Mol. Sci. 2018 19 11 3491 3525 10.3390/ijms19113491 30404198
    [Google Scholar]
  76. Hassanpour S.H. Dehghani M. Review of cancer from perspective of molecular. J. Cancer Res. Pract. 2017 4 4 127 129 10.1016/j.jcrpr.2017.07.001
    [Google Scholar]
  77. Stefani C. Miricescu D. Stanescu-Spinu I.I. Nica R.I. Greabu M. Totan A.R. Jinga M. Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now? Int. J. Mol. Sci. 2021 22 19 10260 10283 10.3390/ijms221910260 34638601
    [Google Scholar]
  78. Huang Y. Zhang Y. Ge L. Lin Y. Kwok H. The roles of protein tyrosine phosphatases in hepatocellular carcinoma. Cancers 2018 10 82 102 10.3390/cancers10030082
    [Google Scholar]
  79. Yuan K. Shen H. Zheng M. Xia F. Li Q. Chen W. Ji M. Yang H. Zhuang X. Cai Z. Min W. Wang X. Xiao Y. Yang P. Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer. J. Med. Chem. 2023 66 6 4215 4230 10.1021/acs.jmedchem.3c00106 36800260
    [Google Scholar]
  80. Siveen K.S. Prabhu K.S. Achkar I.W. Kuttikrishnan S. Shyam S. Khan A.Q. Merhi M. Dermime S. Uddin S. Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products. Mol. Cancer 2018 17 1 31 10.1186/s12943‑018‑0788‑y 29455667
    [Google Scholar]
  81. Cordover E. Minden A. Signaling pathways downstream to receptor tyrosine kinases: targets for cancer treatment. J Cancer Metastasis Treat. 2020 6 45 10.20517/2394‑4722.2020.101
    [Google Scholar]
  82. Metibemu D.S. Akinloye O.A. Akamo A.J. Ojo D.A. Okeowo O.T. Omotuyi I.O. Exploring receptor tyrosine kinases-inhibitors in Cancer treatments. Egypt. J. Med. Hum. Genet. 2019 20 1 35 10.1186/s43042‑019‑0035‑0
    [Google Scholar]
  83. Shyam Sunder S. Sharma U.C. Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct. Target. Ther. 2023 8 1 262 10.1038/s41392‑023‑01469‑6 37414756
    [Google Scholar]
  84. Santorsola M. Capuozzo M. Nasti G. Sabbatino F. Di Mauro A. Di Mauro G. Vanni G. Maiolino P. Correra M. Granata V. Gualillo O. Berretta M. Ottaiano A. Exploring the spectrum of vegf inhibitors’ toxicities from systemic to intra-vitreal usage in medical practice. Cancers 2024 16 350 378 10.3390/cancers16020350
    [Google Scholar]
  85. Soverini S. Rosti G. Iacobucci I. Baccarani M. Martinelli G. Choosing the best second-line tyrosine kinase inhibitor in imatinib-resistant chronic myeloid leukemia patients harboring Bcr-Abl kinase domain mutations: how reliable is the IC₅₀? Oncologist 2011 16 6 868 876 10.1634/theoncologist.2010‑0388 21632458
    [Google Scholar]
  86. Roskoski R. Jr Cost in the United States of FDA-approved small molecule protein kinase inhibitors used in the treatment of neoplastic and non-neoplastic diseases. Pharmacol. Res. 2024 199 107036 10.1016/j.phrs.2023.107036 38096958
    [Google Scholar]
  87. Naufal M. Hermawati E. Syah Y.M. Hidayat A.T. Hidayat I.W. Al-Anshori J. Structure–Activity Relationship Study and Design Strategies of Hydantoin, Thiazolidinedione, and Rhodanine-Based Kinase Inhibitors: A Two-Decade Review. ACS Omega 2024 9 4 4186 4209 10.1021/acsomega.3c04749 38313530
    [Google Scholar]
  88. Azevedo A. Silva S. Rueff J. Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies. Tyrosine Kinases as Druggable Targets Cancer. IntechOpen 2019 5772 10.5772/intechopen.84873
    [Google Scholar]
  89. Jerin S. Harvey A.J. Lewis A. Therapeutic potential of protein tyrosine kinase 6 in colorectal cancer. Cancers 2023 15 14 3703
    [Google Scholar]
  90. Lowe J. Joseph R.E. Andreotti A.H. Conformational switches that control the TEC kinase – PLCγ signaling axis. J. Struct. Biol. X 2022 6 100061 10.1016/j.yjsbx.2022.100061 35128378
    [Google Scholar]
  91. Bedada T. Tyrosine kinase as target for cancer treatment. Int. J. Pharm. Sci. Res. 2014 5 1 1 15 10.13040/IJPSR.0975‑8232.5(1).1‑15
    [Google Scholar]
  92. Pollard D.J. Berger C.N. So E.C. Yu L. Hadavizadeh K. Jennings P. Tate E.W. Choudhary J.S. Frankel G. Broad-spectrum regulation of nonreceptor tyrosine kinases by the bacterial ADP-Ribosyltransferase EspJ. MBio 2018 9 2 e00170-18 10.1128/mBio.00170‑18 29636436
    [Google Scholar]
  93. Serda M. Malarz K. Mrozek-Wilczkiewicz A. Wojtyniak M. Musioł R. Curley S.A. Glycofullerenes as non-receptor tyrosine kinase inhibitors- towards better nanotherapeutics for pancreatic cancer treatment. Sci. Rep. 2020 10 1 260 10.1038/s41598‑019‑57155‑7 31937861
    [Google Scholar]
  94. Malnassy G. Keating C.R. Gad S. Bridgeman B. Perera A. Hou W. Cotler S.J. Ding X. Choudhry M. Sun Z. Koleske A.J. Qiu W. Inhibition of Abelson Tyrosine-Protein Kinase 2 Suppresses the Development of Alcohol-Associated Liver Disease by Decreasing PPARgamma Expression. Cell. Mol. Gastroenterol. Hepatol. 2023 16 5 685 709 10.1016/j.jcmgh.2023.07.006 37460041
    [Google Scholar]
  95. Abernathy-Carver K.J. Liu A. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X- linked agammaglobulinemia. Pediatrics 1994 94 2 280 280 10.1542/peds.94.2.280
    [Google Scholar]
  96. Uckun F.M. Venkatachalam T. Targeting Solid Tumors With B.T.K. Inhibitors. Front. Cell Dev. Biol. 2021 9 650414 10.3389/fcell.2021.650414 33937249
    [Google Scholar]
  97. Darwiche W. Gubler B. Marolleau J.P. Ghamlouch H. Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective. Front. Immunol. 2018 9 683 10.3389/fimmu.2018.00683 29670635
    [Google Scholar]
  98. Garg N. Padron E.J. Rammohan K.W. Goodman C.F. Bruton’s tyrosine kinase inhibitors: The next frontier of b-cell-targeted therapies for cancer, autoimmune disorders, and multiple sclerosis. J. Clin. Med. 2022 11 20 6139 10.3390/jcm11206139 36294458
    [Google Scholar]
  99. Palma M. Mulder T.A. Österborg A. BTK inhibitors in chronic lymphocytic leukemia: biological activity and immune effects. Front. Immunol. 2021 12 686768 10.3389/fimmu.2021.686768 34276674
    [Google Scholar]
  100. Liu H. Qu M. Xu L. Han X. Wang C. Shu X. Yao J. Liu K. Peng J. Li Y. Ma X. Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton’s tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia. Eur. J. Med. Chem. 2017 135 60 69 10.1016/j.ejmech.2017.04.037 28432946
    [Google Scholar]
  101. Zhang Q. Zhang L. Yu J. Li H. He S. Tang W. Zuo J. Lu W. Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold. RSC Advances 2017 7 42 26060 26069 10.1039/C7RA04261B
    [Google Scholar]
  102. Norman P. Investigational Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Expert Opin. Investig. Drugs 2016 25 8 891 899 10.1080/13543784.2016.1182499 27148767
    [Google Scholar]
  103. Li X. Shi B. Teng Y. Cheng Y. Yang H. Li J. Wang L. He S. You Q. Xiang H. Design, synthesis and biological evaluation of novel 2-phenyl pyrimidine derivatives as potent Bruton’s tyrosine kinase (BTK) inhibitors. MedChemComm 2019 10 2 294 299 10.1039/C8MD00413G 30881616
    [Google Scholar]
  104. Kabirova M. Reichenstein M. Borovok N. Sheinin A. Gorobets D. Michaelevski I. Abl2 Kinase Differentially Regulates iGluRs Current Activity and Synaptic Localization. Cell. Mol. Neurobiol. 2023 43 6 2785 2799 10.1007/s10571‑023‑01317‑9 36689065
    [Google Scholar]
  105. Luttman J.H. Colemon A. Mayro B. Pendergast A.M. Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade. Cell Commun. Signal. 2021 19 1 59 10.1186/s12964‑021‑00739‑6 34022881
    [Google Scholar]
  106. Wang J. Pendergast A.M. The emerging role of ABL kinases in solid tumors. Trend. Cancer. 2015 1 110 123 10.1016/j.trecan.2015.07.004
    [Google Scholar]
  107. Li R. Li Q. Ji Q. Molecular targeted study in tumors: From western medicine to active ingredients of traditional Chinese medicine. Biomed. Pharmacother. 2020 121 109624 10.1016/j.biopha.2019.109624 31733579
    [Google Scholar]
  108. Cuellar S. Vozniak M. Rhodes J. Forcello N. Olszta D. BCR-ABL1 tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. J. Oncol. Pharm. Pract. 2018 24 6 433 452 10.1177/1078155217710553 28580869
    [Google Scholar]
  109. Pimentel L.C.F. Hoelz L.V.B. Canzian H.F. Branco F.S.C. de Oliveira A.P. Campos V.R. Júnior F.P.S. Dantas R.F. Resende J.A.L.C. Cunha A.C. Boechat N. Bastos M.M. (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia. Beilstein J. Org. Chem. 2021 17 2260 2269 10.3762/bjoc.17.144 34621389
    [Google Scholar]
  110. Kantankar A. Jayaprakash Rao Y. Mallikarjun G. Hemasri Y. Kethiri R.R. Rational design, synthesis, biological evaluation and molecular docking studies of chromone-pyrimidine derivatives as potent anti-cancer agents. J. Mol. Struct. 2021 1239 130502 10.1016/j.molstruc.2021.130502
    [Google Scholar]
  111. Wang D.P. Wu L.H. Li R. He N. Zhang Q.Y. Zhao C.Y. Jiang T. A Novel Aldisine Derivative Exhibits Potential Antitumor Effects by Targeting JAK/STAT3 Signaling. Mar. Drugs 2023 21 4 218 10.3390/md21040218 37103357
    [Google Scholar]
  112. O’Sullivan J.M. Mead A.J. Psaila B. Single-cell methods in myeloproliferative neoplasms: old questions, new technologies. Blood 2023 141 4 380 390 10.1182/blood.2021014668 36322938
    [Google Scholar]
  113. Bose S. Banerjee S. Mondal A. Chakraborty U. Pumarol J. Croley C.R. Bishayee A. Targeting the JAK/STAT signaling pathway using phytocompounds for cancer prevention and therapy. Cells. 2020 9 1451 10.3390/cells9061451
    [Google Scholar]
  114. Yang T. Hu M. Chen Y. Xiang M. Tang M. Qi W. Shi M. He J. Yuan X. Zhang C. Liu K. Li J. Yang Z. Chen L. N -(Pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Derivatives as Selective Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms. J. Med. Chem. 2020 63 23 14921 14936 10.1021/acs.jmedchem.0c01488 33256400
    [Google Scholar]
  115. Elmongy E. Henidi H. In Silico evaluation of a promising key intermediate thieno [2,3-d] pyrimidine derivative with expected JAK2 Kinase Inhibitory Activity. Molbank 2022 2022 1 M1352 M1361 10.3390/M1352
    [Google Scholar]
  116. Chuang H.H. Zhen Y.Y. Tsai Y.C. Chuang C.H. Hsiao M. Huang M.S. Yang C.J. FAK in Cancer: From Mechanisms to Therapeutic Strategies. Int. J. Mol. Sci. 2022 23 3 1726 10.3390/ijms23031726 35163650
    [Google Scholar]
  117. Lim S.T. Chen X.L. Lim Y. Hanson D.A. Vo T.T. Howerton K. Larocque N. Fisher S.J. Schlaepfer D.D. Ilic D. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell 2008 29 1 9 22 10.1016/j.molcel.2007.11.031 18206965
    [Google Scholar]
  118. Bullard Dunn K. Heffler M. Golubovskaya V.M. Evolving Therapies and FAK Inhibitors for the Treatment of Cancer, Anticancer Agents. Med. Chem. 2010 10 722 734 10.2174/187152010794728657
    [Google Scholar]
  119. Wang R. Chen Y. Zhao X. Yu S. Yang B. Wu T. Guo J. Hao C. Zhao D. Cheng M. Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents. Eur. J. Med. Chem. 2019 183 111716 10.1016/j.ejmech.2019.111716 31550660
    [Google Scholar]
  120. Wang S. Zhang R.H. Zhang H. Wang Y.C. Yang D. Zhao Y.L. Yan G.Y. Xu G.B. Guan H.Y. Zhou Y.H. Cui D.B. Liu T. Li Y.J. Liao S.G. Zhou M. Design, synthesis, and biological evaluation of 2,4-diamino pyrimidine derivatives as potent FAK inhibitors with anti-cancer and anti-angiogenesis activities. Eur. J. Med. Chem. 2021 222 113573 10.1016/j.ejmech.2021.113573 34091209
    [Google Scholar]
  121. Du Z. Lovly C.M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer 2018 17 1 58 10.1186/s12943‑018‑0782‑4 29455648
    [Google Scholar]
  122. Mahato A.K. Sidorova Y.A. RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer. Int. J. Mol. Sci. 2020 21 19 7108 10.3390/ijms21197108 32993133
    [Google Scholar]
  123. Ullo M.F. Case L.B. How cells sense and integrate information from different sources. WIREs Mech. Dis. 2023 15 4 e1604 10.1002/wsbm.1604 36781396
    [Google Scholar]
  124. Gligorijević N. Dobrijević Z. Šunderić M. Robajac D. Četić D. Penezić A. Miljuš G. Nedić O. The insulin-like growth factor system and colorectal cancer. Life 2022 12 1274 10.3390/life12081274
    [Google Scholar]
  125. Vasilogianni A.M. Al-Majdoub Z.M. Achour B. Peters S.A. Rostami-Hodjegan A. Barber J. Proteomic quantification of receptor tyrosine kinases involved in the development and progression of colorectal cancer liver metastasis. Front. Oncol. 2023 13 1010563 10.3389/fonc.2023.1010563 36890818
    [Google Scholar]
  126. Zhao M. Jung Y. Jiang Z. Svensson K.J. Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands. Front. Physiol. 2020 11 354 10.3389/fphys.2020.00354 32372975
    [Google Scholar]
  127. Ségaliny A.I. Tellez-Gabriel M. Heymann M.F. Heymann D. Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers. J. Bone Oncol. 2015 4 1 1 12 10.1016/j.jbo.2015.01.001 26579483
    [Google Scholar]
  128. Guo G. Gong K. Wohlfeld B. Hatanpaa K.J. Zhao D. Habib A.A. Ligand-Independent EGFR Signaling. Cancer Res. 2015 75 17 3436 3441 10.1158/0008‑5472.CAN‑15‑0989 26282175
    [Google Scholar]
  129. Sigismund S. Avanzato D. Lanzetti L. Emerging functions of the EGFR in cancer. Mol. Oncol. 2018 12 1 3 20 10.1002/1878‑0261.12155 29124875
    [Google Scholar]
  130. Raymond E. Faivre S. Armand J.P. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 2000 60 Suppl. 1 15 23 10.2165/00003495‑200060001‑00002 11129168
    [Google Scholar]
  131. Wee P. Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel) 2017 9 5 52 10.3390/cancers9050052 28513565
    [Google Scholar]
  132. Hopper-Borge E.A. Nasto R.E. Ratushny V. Weiner L.M. Golemis E.A. Astsaturov I. Mechanisms of tumor resistance to EGFR-targeted therapies. Expert Opin. Ther. Targets 2009 13 3 339 362 10.1517/14712590902735795 19236156
    [Google Scholar]
  133. Lindsey S. Langhans S.A. Epidermal Growth Factor Signaling in Transformed Cells. Int. Rev. Cell Mol. Biol 2015 1 41 10.1016/bs.ircmb.2014.10.001
    [Google Scholar]
  134. Al-Anazi M. Khairuddean M. Al-Najjar B.O. Murwih Alidmat M. Nur Syazni Nik Mohamed Kamal N. Muhamad M. Synthesis, anticancer activity and docking studies of pyrazoline and pyrimidine derivatives as potential epidermal growth factor receptor (EGFR) inhibitors. Arab. J. Chem. 2022 15 103864 10.1016/j.arabjc.2022.103864
    [Google Scholar]
  135. Sudhesh Dev S. Zainal Abidin S.A. Farghadani R. Othman I. Naidu R. Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer. Front. Pharmacol. 2021 12 772510 10.3389/fphar.2021.772510 34867402
    [Google Scholar]
  136. Drugs@FDA: FDA-Approved Drugs. 2010 Available from:https://www.fda.gov/drugsatfda(accessed on 23-10-2024)
  137. Ahmed N.M. Youns M.M. Soltan M.K. Said A.M. Design, Synthesis, Molecular Modeling and Antitumor Evaluation of novel indolyl-pyrimidine derivatives with EGFR inhibitory activity. Molecules 2021 26 7 1838 1856 10.3390/molecules26071838 33805918
    [Google Scholar]
  138. Osman I.A. Ayyad R.R. Mahdy H.A. New pyrimidine-5-carbonitrile derivatives as EGFR inhibitors with anticancer and apoptotic activities: design, molecular modeling and synthesis. New J. Chem. 2022 46 24 11812 11827 10.1039/D2NJ01451C
    [Google Scholar]
  139. Sobh E.A. Dahab M.A. Elkaeed E.B. Alsfouk A.A. Ibrahim I.M. Metwaly A.M. Eissa I.H. Computer aided drug discovery (CADD) of a thieno[2,3- d ]pyrimidine derivative as a new EGFR inhibitor targeting the ribose pocket. J. Biomol. Struct. Dyn. 2024 42 5 2369 2391 10.1080/07391102.2023.2204500 37129193
    [Google Scholar]
  140. Sobh E.A. Dahab M.A. Elkaeed E.B. Alsfouk A.A. Ibrahim I.M. Metwaly A.M. Eissa I.H. Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3- d ]pyrimidine derivatives as new EGFR inhibitors. J. Enzyme Inhib. Med. Chem. 2023 38 1 2220579 10.1080/14756366.2023.2220579 37288786
    [Google Scholar]
  141. Mohammadzadeh P. Amberg G.C. AXL/Gas6 signaling mechanisms in the hypothalamic-pituitary-gonadal axis. Front. Endocrinol. (Lausanne) 2023 14 1212104 10.3389/fendo.2023.1212104 37396176
    [Google Scholar]
  142. Zhong F. Cai H. Fu J. Sun Z. Li Z. Bauman D. Wang L. Das B. Lee K. He J.C. TYRO3 agonist as therapy for glomerular disease. JCI Insight 2023 8 1 e165207 10.1172/jci.insight.165207 36454644
    [Google Scholar]
  143. Tutusaus A. Marí M. Ortiz-Pérez J.T. Nicolaes G.A.F. Morales A. García de Frutos P. Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis. Cells 2020 9 10 2186 10.3390/cells9102186 32998369
    [Google Scholar]
  144. Vago J.P. Amaral F.A. van de Loo F.A.J. Resolving inflammation by TAM receptor activation. Pharmacol. Ther. 2021 227 107893 10.1016/j.pharmthera.2021.107893 33992683
    [Google Scholar]
  145. Aehnlich P. Powell R.M. Peeters M.J.W. Rahbech A. thor Straten P. TAM Receptor Inhibition–Implications for Cancer and the Immune System. Cancers (Basel) 2021 13 6 1195 10.3390/cancers13061195 33801886
    [Google Scholar]
  146. Antony J. Huang R.Y.J. AXL-Driven EMT State as a Targetable Conduit in Cancer. Cancer Res. 2017 77 14 3725 3732 10.1158/0008‑5472.CAN‑17‑0392 28667075
    [Google Scholar]
  147. Akalu Y.T. Rothlin C.V. Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol. Rev. 2017 276 1 165 177 10.1111/imr.12522 28258690
    [Google Scholar]
  148. Kim D. Lee K.W. Jung H. Kim M. Lee J.Y. Lee Y. Hwang J.Y. Min Y. Lee C.H. Cho S.Y. Design and Synthesis of Novel 2,4‐Diamino‐5‐pyrazol‐4‐yl Pyrimidine Derivatives as Selective Tyro3 Kinase Inhibitors. Bull. Korean Chem. Soc. 2018 39 9 1101 1104 10.1002/bkcs.11541
    [Google Scholar]
  149. Kim Y. Lee K.W. Yeom H. Kim M. Lee Y.K. Lee J.Y. Hwang J.Y. Min Y. Ryu D.H. Lee C.H. Cho S.Y. Design and Synthesis of 5‐Aryl ‐substituted Phenylpyrimidine‐2,4‐diamine Derivatives as Novel Mer and Tyro3 Kinase Inhibitors. Bull. Korean Chem. Soc. 2021 42 2 206 211 10.1002/bkcs.12167
    [Google Scholar]
  150. Xu D. Sun D. Wang W. Peng X. Zhan Z. Ji Y. Shen Y. Geng M. Ai J. Duan W. Discovery of pyrrolo[2,3-d]pyrimidine derivatives as potent Axl inhibitors: Design, synthesis and biological evaluation. Eur. J. Med. Chem. 2021 220 113497 10.1016/j.ejmech.2021.113497 33957388
    [Google Scholar]
  151. Stuttfeld E. Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life 2009 61 9 915 922 10.1002/iub.234 19658168
    [Google Scholar]
  152. Wang X. Bove A.M. Simone G. Ma B. Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role. Front. Cell Dev. Biol. 2020 8 599281 10.3389/fcell.2020.599281 33304904
    [Google Scholar]
  153. Zheng Q. Hou W. Regulation of angiogenesis by microRNAs in cancer. Mol. Med. Rep. 2021 24 2 583 10.3892/mmr.2021.12222 34132365
    [Google Scholar]
  154. Sayed M.T.M. Halim P.A. El-Ansary A.K. Hassan R.A. Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3‐ d ]pyrimidine derivatives as EGFR inhibitors. Drug Dev. Res. 2023 84 6 1299 1319 10.1002/ddr.22088 37357422
    [Google Scholar]
  155. Inai T. Mancuso M. Hashizume H. Baffert F. Haskell A. Baluk P. Hu-Lowe D.D. Shalinsky D.R. Thurston G. Yancopoulos G.D. McDonald D.M. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 2004 165 1 35 52 10.1016/S0002‑9440(10)63273‑7 15215160
    [Google Scholar]
  156. Ruzi Z. Bozorov K. Nie L. Zhao J. Aisa H.A. Novel pyrazolo[3,4-d]pyrimidines as potential anticancer agents: Synthesis, VEGFR-2 inhibition, and mechanisms of action. Biomed. Pharmacother. 2022 156 113948 10.1016/j.biopha.2022.113948 36411633
    [Google Scholar]
  157. Hassan R.A. Hamed M.I.A. Abdou A.M. El-Dash Y. Novel antiproliferative agents bearing substituted thieno[2,3-d]pyrimidine scaffold as dual VEGFR-2 and BRAF kinases inhibitors and apoptosis inducers; design, synthesis and molecular docking. Bioorg. Chem. 2022 125 105861 10.1016/j.bioorg.2022.105861 35569190
    [Google Scholar]
  158. Seif S.E. Mahmoud Z. Wardakhan W.W. Abdou A.M. Hassan R.A. Design and synthesis of novel hexahydrobenzo[4,5]thieno[2,3‐ d ]pyrimidine derivatives as potential anticancer agents with antiangiogenic activity via VEGFR‐2 inhibition, and down‐regulation of PI3K/AKT/mTOR signaling pathway. Drug Dev. Res. 2023 84 5 839 860 10.1002/ddr.22058 37016480
    [Google Scholar]
  159. Karim M. Saul S. Ghita L. Sahoo M.K. Ye C. Bhalla N. Lo C.W. Jin J. Park J.G. Martinez-Gualda B. East M.P. Johnson G.L. Pinsky B.A. Martinez-Sobrido L. Asquith C.R.M. Narayanan A. De Jonghe S. Einav S. Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies. Antiviral Res. 2022 204 105367 10.1016/j.antiviral.2022.105367 35738348
    [Google Scholar]
  160. Wang J. Ji X. Liu J. Zhang X. Serine/Threonine Protein Kinase STK16. Int. J. Mol. Sci. 2019 20 7 1760 10.3390/ijms20071760 30974739
    [Google Scholar]
  161. Mei L. Zhang J. He K. Zhang J. Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand. J. Hematol. Oncol. 2019 12 1 43 10.1186/s13045‑019‑0733‑6 31018854
    [Google Scholar]
  162. Łukasik P. Załuski M. Gutowska I. Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development–Review. Int. J. Mol. Sci. 2021 22 6 2935 10.3390/ijms22062935 33805800
    [Google Scholar]
  163. Kohno M. Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann. Med. 2006 38 3 200 211 10.1080/07853890600551037 16720434
    [Google Scholar]
  164. Elgammal W.E. Shaban S.S. Eliwa E.M. Halawa A.H. Abd El-Gilil S.M. Hassan R.A. Abdou A.M. Elhagali G.A.M. Reheim M.A.M.A. Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking. Future Med. Chem. 2024 16 12 1219 1237 10.1080/17568919.2024.2342668 38989988
    [Google Scholar]
  165. Faggal S.I. El-Dash Y. Sonousi A. Abdou A.M. Hassan R.A. Design, synthesis, and biological evaluation of novel thiazole derivatives as PI3K/mTOR dual inhibitors. RSC Med. Chem. 2024 Advance online publication 10.1039/D4MD00462K 39345714
    [Google Scholar]
  166. Xia Y. Schneyer A.L. The biology of activin: recent advances in structure, regulation and function. J. Endocrinol. 2009 202 1 1 12 10.1677/JOE‑08‑0549 19273500
    [Google Scholar]
  167. Wińska P. Wielechowska M. Koronkiewicz M. Borowiecki P. Synthesis and Anticancer Activity of Novel Dual Inhibitors of Human Protein Kinases CK2 and PIM-1. Pharmaceutics 2023 15 7 1991 10.3390/pharmaceutics15071991 37514177
    [Google Scholar]
  168. Liu J. Yang X. Li B. Wang J. Wang W. Liu J. Liu Q. Zhang X. STK16 regulates actin dynamics to control Golgi organization and cell cycle. Sci. Rep. 2017 7 1 44607 10.1038/srep44607 28294156
    [Google Scholar]
  169. Halawa A.H. Eskandrani A.A. Elgammal W.E. Hassan S.M. Hassan A.H. Ebrahim H.Y. Mehany A.B.M. El-Agrody A.M. Okasha R.M. Rational Design and Synthesis of Diverse Pyrimidine Molecules Bearing Sulfonamide Moiety as Novel ERK Inhibitors. Int. J. Mol. Sci. 2019 20 22 5592 5618 10.3390/ijms20225592
    [Google Scholar]
  170. Cherukupalli S. Chandrasekaran B. Aleti R.R. Sayyad N. Hampannavar G.A. Merugu S.R. Rachamalla H.R. Banerjee R. Karpoormath R. Synthesis of 4,6-disubstituted pyrazolo[3,4-d]pyrimidine analogues: Cyclin-dependent kinase 2 (CDK2) inhibition, molecular docking and anticancer evaluation. J. Mol. Struct. 2019 1176 538 551 10.1016/j.molstruc.2018.08.104
    [Google Scholar]
  171. Kovalová M. Havlíček L. Djukic S. Škerlová J. Peřina M. Pospíšil T. Řezníčková E. Řezáčová P. Jorda R. Kryštof V. Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7. Biomed. Pharmacother. 2023 161 114492 10.1016/j.biopha.2023.114492 36931035
    [Google Scholar]
  172. Abdulrahman F.G. Sabour R. El-Gilil S.M.A. Mehany A.B.M. Taha E.A. Design, synthesis, biological evaluation and molecular docking study of new pyrazolo[1,5-a]pyrimidines as PIM kinase inhibitors and apoptosis inducers. J. Mol. Struct. 2024 1295 136811 10.1016/j.molstruc.2023.136811
    [Google Scholar]
  173. Gao X. Zhao F. Wang Y. Ma X. Chai H. Han J. Fang F. Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics. Bioorg. Med. Chem. 2023 91 117402 10.1016/j.bmc.2023.117402 37421709
    [Google Scholar]
  174. Yuan K. Li Z. Kuang W. Wang X. Ji M. Chen W. Ding J. Li J. Min W. Sun C. Ye X. Lu M. Wang L. Ge H. Jiang Y. Hao H. Xiao Y. Yang P. Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer. Nat. Commun. 2022 13 1 2903 10.1038/s41467‑022‑30581‑4 35614066
    [Google Scholar]
  175. Boni J. Rubio-Perez C. López-Bigas N. Fillat C. de la Luna S. The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities. Cancers (Basel) 2020 12 8 2106 10.3390/cancers12082106 32751160
    [Google Scholar]
  176. Lindberg M.F. Meijer L. Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview. Int. J. Mol. Sci. 2021 22 11 6047 10.3390/ijms22116047 34205123
    [Google Scholar]
  177. Kamioka H. Yogosawa S. Oikawa T. Aizawa D. Ueda K. Saeki C. Haruki K. Shimoda M. Ikegami T. Nishikawa Y. Saruta M. Yoshida K. Dyrk2 gene transfer suppresses hepatocarcinogenesis by promoting the degradation of Myc and Hras. JHEP Rep. Innov. Hepatol. 2023 5 7 100759 10.1016/j.jhepr.2023.100759 37333975
    [Google Scholar]
  178. Hainer S.J. Martens J.A. Identification of histone mutants that are defective for transcription-coupled nucleosome occupancy. Mol. Cell. Biol. 2011 31 17 3557 3568 10.1128/MCB.05195‑11 21730290
    [Google Scholar]
  179. Sehrawat P. Shobhawat R. Kumar A. Catching Nucleosome by Its Decorated Tails Determines Its Functional States. Front. Genet. 2022 13 903923 10.3389/fgene.2022.903923 35910215
    [Google Scholar]
  180. Santos-Rosa H. Millán-Zambrano G. Han N. Leonardi T. Klimontova M. Nasiscionyte S. Pandolfini L. Tzelepis K. Bartke T. Kouzarides T. Methylation of histone H3 at lysine 37 by Set1 and Set2 prevents spurious DNA replication. Mol. Cell 2021 81 13 2793 2807.e8 10.1016/j.molcel.2021.04.021 33979575
    [Google Scholar]
  181. Li G. Tian Y. Zhu W.G. The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy. Front. Cell Dev. Biol. 2020 8 576946 10.3389/fcell.2020.576946 33117804
    [Google Scholar]
  182. Li Y. Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb. Perspect. Med. 2016 6 10 a026831 10.1101/cshperspect.a026831 27599530
    [Google Scholar]
  183. Choi M.A. Park S.Y. Chae H.Y. Song Y. Sharma C. Seo Y.H. Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes. Sci. Rep. 2019 9 1 13187 10.1038/s41598‑019‑49784‑9 31515509
    [Google Scholar]
  184. Mehmood S.A. Sahu K.K. Sengupta S. Partap S. Karpoormath R. Kumar B. Kumar D. Recent advancement of HDAC inhibitors against breast cancer. Med. Oncol. 2023 40 7 201 10.1007/s12032‑023‑02058‑x 37294406
    [Google Scholar]
  185. Moya-García A.A. Pino-Ángeles A. Gil-Redondo R. Morreale A. Jiménez F. Structural features of mammalian histidine decarboxylase reveal the basis for specific inhibition. Br. J. Pharmacol. 2009 157 1 4 13 10.1111/j.1476‑5381.2009.00219.x 19413567
    [Google Scholar]
  186. Arora S. Yang J-M. Utsumi R. Okamoto T. Kitayama T. Hait W.N. P-glycoprotein mediates resistance to histidine kinase inhibitors. Mol. Pharmacol. 2004 66 3 460 467 10.1124/mol.66.3 15322237
    [Google Scholar]
  187. Chen D. Soh C.K. Goh W.H. Wang H. Design, synthesis, and preclinical evaluation of fused pyrimidine-based hydroxamates for the treatment of hepatocellular carcinoma. J. Med. Chem. 2018 61 4 1552 1575 10.1021/acs.jmedchem.7b01465 29360358
    [Google Scholar]
  188. Xing K. Zhang J. Han Y. Tong T. Liu D. Zhao L. Design, Synthesis and Bioactivity Evaluation of 4,6-Disubstituted Pyrido[3,2-d]pyrimidine Derivatives as Mnk and HDAC Inhibitors. Molecules 2020 25 18 4318 10.3390/molecules25184318 32967084
    [Google Scholar]
/content/journals/cpd/10.2174/0113816128346900241111115125
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  • Article Type:
    Review Article
Keywords: protein kinase inhibitors ; Pyrimidine nucleus ; anticancer
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