Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents)
  4. Volume 24, Issue 6
  5. Article
Volume 24, Issue 6
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Background

Efficient targeted molecular therapeutics are needed for the treatment of triple-negative breast cancer (TNBC), a highly invasive and difficult-to-treat form of breast cancer associated with a poor prognosis.

Objectives

This study aims to evaluate the potential of selective CDK4/6 inhibitors as a therapeutic option for TNBC by impairing the cell cycle G1 phase through the inhibition of retinoblastoma protein (Rb) phosphorylation.

Methods

In this study, we synthesized a compound called JHD205, derived from the chemical structure of Abemaciclib, and examined its inhibitory effects on the malignant characteristics of TNBC cells.

Results

Our results demonstrated that JHD205 exhibited superior tumor growth inhibition compared to Abemaciclib in breast cancer xenograft chicken embryo models. Western blot analysis revealed that JHD205 could dose-dependently degrade CDK4 and CDK6 while also causing abnormal changes in other proteins associated with CDK4/6, such as p-Rb, Rb, and E2F1. Moreover, JHD205 induced apoptosis and DNA damage and inhibited DNA repair by upregulating Caspase3 and p-H2AX protein levels.

Conclusion

Collectively, our findings suggest that JHD205 holds promise as a potential treatment for breast carcinoma.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/acamc/10.2174/0118715206265751231204190204
2024-04-01
2025-04-15

  • From This Site

    /content/journals/acamc/10.2174/0118715206265751231204190204
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Erratum: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202070431310.3322/caac.2160932767693
     [Google Scholar]
  2. RyuD.W. JungM.J. ChoiW.S. LeeC.H. Clinical significance of morphologic characteristics in triple negative breast cancer.J. Korean Surg. Soc.201180530130610.4174/jkss.2011.80.5.30122066052
     [Google Scholar]
  3. SiegelR.L. MillerK.D. JemalA. Cancer statistics, 2019.CA Cancer J. Clin.201969173410.3322/caac.2155130620402
     [Google Scholar]
  4. VagiaE. MahalingamD. CristofanilliM. The landscape of targeted therapies in TNBC.Cancers202012491610.3390/cancers1204091632276534
     [Google Scholar]
  5. JiJ. LiuW. XuY. XuZ. LvM. FengJ. LvJ. HeX. ZhangZ. XieM. JingA. WangX. MaJ. LiuB. WXJ-202, a novel Ribociclib derivative, exerts antitumor effects against breast cancer through CDK4/6.Front. Pharmacol.202313107219410.3389/fphar.2022.107219436744210
     [Google Scholar]
  6. DicksonM.A. Molecular pathways: CDK4 inhibitors for cancer therapy.Clin. Cancer Res.201420133379338310.1158/1078‑0432.CCR‑13‑155124795392
     [Google Scholar]
  7. SpringL.M. WanderS.A. ZangardiM. BardiaA. CDK 4/6 inhibitors in breast cancer: Current controversies and future directions.Curr. Oncol. Rep.20192132510.1007/s11912‑019‑0769‑330806829
     [Google Scholar]
  8. BurkhartD.L. SageJ. Cellular mechanisms of tumour suppression by the retinoblastoma gene.Nat. Rev. Cancer20088967168210.1038/nrc239918650841
     [Google Scholar]
  9. WitkiewiczA.K. ErtelA. McFallsJ. ValsecchiM.E. SchwartzG. KnudsenE.S. RB-pathway disruption is associated with improved response to neoadjuvant chemotherapy in breast cancer.Clin. Cancer Res.201218185110512210.1158/1078‑0432.CCR‑12‑090322811582
     [Google Scholar]
  10. WitkiewiczA.K. BalajiU. EslingerC. McMillanE. ConwayW. PosnerB. MillsG.B. O’ReillyE.M. KnudsenE.S. Integrated patient-derived models delineate individualized therapeutic vulnerabilities of pancreatic cancer.Cell Rep.20161672017203110.1016/j.celrep.2016.07.02327498862
     [Google Scholar]
  11. NebenfuehrS. KollmannK. SexlV. The role of CDK6 in cancer.Int. J. Cancer2020147112988299510.1002/ijc.3305432406095
     [Google Scholar]
  12. GoelS. BergholzJ.S. ZhaoJ.J. Targeting CDK4 and CDK6 in cancer.Nat. Rev. Cancer202222635637210.1038/s41568‑022‑00456‑335304604
     [Google Scholar]
  13. KhleifS.N. DeGregoriJ. YeeC.L. OttersonG.A. KayeF.J. NevinsJ.R. HowleyP.M. Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity.Proc. Natl. Acad. Sci. USA19969394350435410.1073/pnas.93.9.43508633069
     [Google Scholar]
  14. SlamonD.J. NevenP. ChiaS. JerusalemG. De LaurentiisM. Im, S.; Petrakova, K.; Valeria Bianchi, G.; Martín, M.; Nusch, A.; Sonke, G.S.; De la Cruz-Merino, L.; Beck, J.T.; Ji, Y.; Wang, C.; Deore, U.; Chakravartty, A.; Zarate, J.P.; Taran, T.; Fasching, P.A. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.Ann. Oncol.20213281015102410.1016/j.annonc.2021.05.35334102253
     [Google Scholar]
  15. SlamonD.J. NevenP. ChiaS. FaschingP.A. De LaurentiisM. Im, S.A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Martín, M.; Nusch, A.; Sonke, G.S.; De la Cruz-Merino, L.; Beck, J.T.; Pivot, X.; Vidam, G.; Wang, Y.; Rodriguez Lorenc, K.; Miller, M.; Taran, T.; Jerusalem, G. Phase III randomized study of Ribociclib and Fulvestrant in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: MONALEESA-3.J. Clin. Oncol.201836242465247210.1200/JCO.2018.78.990929860922
     [Google Scholar]
  16. SledgeG.W.Jr ToiM. NevenP. SohnJ. InoueK. PivotX. BurdaevaO. OkeraM. MasudaN. KaufmanP.A. KohH. GrischkeE.M. FrenzelM. LinY. BarrigaS. SmithI.C. BourayouN. Llombart-CussacA. MONARCH 2: Abemaciclib in combination with fulvestrant in women With HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy.J. Clin. Oncol.201735252875288410.1200/JCO.2017.73.758528580882
     [Google Scholar]
  17. LehmannB.D. BauerJ.A. ChenX. SandersM.E. ChakravarthyA.B. ShyrY. PietenpolJ.A. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.J. Clin. Invest.201112172750276710.1172/JCI4501421633166
     [Google Scholar]
  18. AsgharU.S. BarrA.R. CuttsR. BeaneyM. BabinaI. SampathD. GiltnaneJ. LacapJ.A. CrockerL. YoungA. PearsonA. Herrera-AbreuM.T. BakalC. TurnerN.C. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer.Clin. Cancer Res.201723185561557210.1158/1078‑0432.CCR‑17‑036928606920
     [Google Scholar]
  19. BoscoE.E. KnudsenE.S. RB in breast cancer: At the crossroads of tumorigenesis and treatment.Cell Cycle20076666767110.4161/cc.6.6.398817361100
     [Google Scholar]
  20. WeintraubS.J. PraterC.A. DeanD.C. Retinoblastoma protein switches the E2F site from positive to negative element.Nature1992358638325926110.1038/358259a01321348
     [Google Scholar]
  21. LimS. KaldisP. Cdks, cyclins and CKIs: Roles beyond cell cycle regulation.Development2013140153079309310.1242/dev.09174423861057
     [Google Scholar]
  22. GaoX. LeoneG.W. WangH. Cyclin D-CDK4/6 functions in cancer.Adv. Cancer Res.202014814716910.1016/bs.acr.2020.02.00232723562
     [Google Scholar]
  23. NebenfuehrS. BelluttiF. SexlV. Cdk6: At the interface of Rb and p53.Mol. Cell. Oncol.201855e151120610.1080/23723556.2018.151120630263948
     [Google Scholar]
  24. LiaoC.C. TsaiC.Y. ChangW.C. LeeW.H. WangJ.M. RBE2F1 complex mediates DNA damage responses through transcriptional regulation of ZBRK1.J. Biol. Chem.201028543331343314310.1074/jbc.M110.14346120713352
     [Google Scholar]
  25. CretellaD. FumarolaC. BonelliM. AlfieriR. La MonicaS. DigiacomoG. CavazzoniA. GalettiM. GeneraliD. PetroniniP.G. Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells.Sci. Rep.2019911301410.1038/s41598‑019‑49484‑431506466
     [Google Scholar]
  26. RoosW.P. ThomasA.D. KainaB. DNA damage and the balance between survival and death in cancer biology.Nat. Rev. Cancer2016161203310.1038/nrc.2015.226678314
     [Google Scholar]
  27. WangY. LuoW. WangY. PARP-1 and its associated nucleases in DNA damage response.DNA Repair20198110265110.1016/j.dnarep.2019.10265131302005
     [Google Scholar]
  28. VaitsiankovaA. BurdovaK. SobolM. GautamA. BenadaO. HanzlikovaH. CaldecottK.W. PARP inhibition impedes the maturation of nascent DNA strands during DNA replication.Nat. Struct. Mol. Biol.202229432933810.1038/s41594‑022‑00747‑135332322
     [Google Scholar]
  29. LeiS. GeF. LinM. WangX. ShenJ. YangY. DengJ. WangZ. WangJ. LiK. PARP inhibitors diminish DNA damage repair for the enhancement of tumor photodynamic therapy.Photodiagn. Photodyn. Ther.20224010305810.1016/j.pdpdt.2022.10305835944846
     [Google Scholar]
  30. HuangP. ChenG. JinW. MaoK. WanH. HeY. Molecular mechanisms of parthanatos and its role in diverse diseases.Int. J. Mol. Sci.20222313729210.3390/ijms2313729235806303
     [Google Scholar]
  31. BurmaS. ChenB.P. MurphyM. KurimasaA. ChenD.J. ATM phosphorylates histone H2AX in response to DNA doublestrand breaks.J. Biol. Chem.200127645424624246710.1074/jbc.C10046620011571274
     [Google Scholar]
  32. DeanJ.L. McClendonA.K. KnudsenE.S. Modification of the DNA damage response by therapeutic CDK4/6 inhibition.J. Biol. Chem.201228734290752908710.1074/jbc.M112.36549422733811
     [Google Scholar]
  33. Salvador-BarberoB. Alvarez-FernándezM. Zapatero-SolanaE. El BakkaliA. MenéndezM.C. López-CasasP.P. Di DomenicoT. XieT. VanArsdaleT. ShieldsD.J. HidalgoM. MalumbresM. CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma.Cancer Cell202038458410.1016/j.ccell.2020.09.01233049208
     [Google Scholar]
  34. CrozierL. FoyR. MoueryB.L. WhitakerR.H. CornoA. SpanosC. LyT. Gowen CookJ. SaurinA.T. CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal.EMBO J.2022416e10859910.15252/embj.202110859935037284
     [Google Scholar]
  35. ZhuX. ChenL. HuangB. LiX. YangL. HuX. JiangY. ShaoZ. WangZ. Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer.J. Exp. Clin. Cancer Res.202140112210.1186/s13046‑021‑01930‑w33832512
     [Google Scholar]
/content/journals/acamc/10.2174/0118715206265751231204190204
Loading
JHD205, A Novel Abemaciclib Derivative, Exerts Antitumor Effects on Breast Cancer by CDK4/6
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) 24, 400 (2024); https://doi.org/10.2174/0118715206265751231204190204
/content/journals/acamc/10.2174/0118715206265751231204190204
/content/journals/acamc/10.2174/0118715206265751231204190204
Loading

Data & Media loading...

Supplements

file format download Download

  • Article Type:     Research Article
Keyword(s): antitumor activity; Breast cancer; CDK4/6; cell phenotype; DNA damage; molecular docking

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test