Recent Patents on Anti-Cancer Drug Discovery - Volume 18, Issue 4, 2023

Background: Cancer is a global health issue and economic burden with a continuous increase in incidence and mortality. Over the years, the underlying molecular mechanism of cancers was thoroughly researched, leading to multiple drugs' development. Unfortunately, most drugs have some serious drawbacks, such as therapy resistance and toxicity. Epidemiological studies have shown that a diet rich in fruits and vegetables has cancer prevention properties, which shifted the attention to the potential role of phytochemicals in anti-carcinogenic activity. Objective: To review the present status of phytochemicals research and patents in cancer prevention and chemosensitization. Methods: We explored the relevant published articles and patents to review the phytochemicals showing cancer preventive role in preclinical settings from 1997 onwards. Results: We summarise the role of phytochemicals on anti-carcinogenic, anti-inflammatory, antiproliferative, anti-metastatic, and pro-apoptotic activities in both in vitro and in vivo. Thus, phytochemicals might be an excellent chemosensitizing agent against chemoresistant cells and possibly one of the safest and most effective options for cancer therapy. However, one of the limitations of phytochemicals is their poor bioavailability and rapid excretion. Several analogs have been introduced to increase bioavailability, better biological efficacy, absorption, and retention. In fact, various phytochemicals and their analogs have been patented for their anti-cancerous properties. Conclusion: This mini-review discusses various phytochemicals and their anti-cancerous and chemosensitizing roles. Due to their clinical relevance, recent trends in phytochemical extraction and exploration have shown that more and more phytochemicals are being patented.

Background: Gefitinib, a tyrosine kinase inhibitor, is effectively used in the targeted treatment of malignant conditions. It suppresses the signal transduction cascades leading to cell proliferation in the tumors and is now currently approved in several countries globally as secondline and third-line treatment for non-small cell lung cancer (NSCLC). Objective: This review is aimed to summarize the journey of gefitinib as an established anticancer drug for the management of various cancers. Moreover, this review will focus on the mechanism of action, established anticancer activities, combination therapy, nanoformulations, as well as recent clinical trials and patents on gefitinib. Methods: The data for this review was collected from scientific databases such as PubMed, Science Direct, Google Scholar, etc. Recent patents on gefitinib granted in the last two years were collected from databases Patentscope, USPTO, Espacenet, InPASS and Google Patents. Data for the recent clinical trials were obtained from the U.S. National Library of Medicine database. Results: Recent pre-clinical and clinical studies during the period 2015-2021 demonstrating the efficacy of gefitinib were selected and summarized. Total 31 patents were granted in the year 2020-2021 concerning gefitinib. The efficacy of gefitinib against lung cancer, as well as other cancer types, including breast, prostate, colon, cervix etc., was reviewed. Conclusion: Gefitinib showed significant advantages in being more effective, safer and more stable, and the associated biopharmaceutical problems are addressed by the application of nanotechnology. The combination therapy using gefitinib and various anticancer molecules of natural and synthetic origin has shown an improved anticancer profile.

Cancer is a leading cause of morbidity and mortality worldwide. Each year, millions of people worldwide are diagnosed with cancer, and more than half of them die. Various conventional therapies for cancer, including chemotherapy and radiotherapy, have extreme side effects. Therefore, to minimize the global burden of lethal diseases like cancer, an effective and novel drug must be discovered. Its patent should be acquired to secure the novel medicament. The pharmacological potential of different natural products has made them popular in the healthcare and pharmaceutical industries. Various anticancer compounds are obtained from natural sources such as plants, microbes, and marine and terrestrial animals, including alkaloids, terpenoids, biophenols, enzymes, glycosides, etc. The term "natural products" is defined as the product of secondary or non-essential metabolic processes produced by living organisms (such as plants, invertebrates, and microorganisms). Although more precise definitions of NPs exist, they do not always meet consensus. Others define NPs as small molecules (excluding biomolecules) that emerge from the metabolic reaction. A handful of effective compounds are used currently from natural or analog moieties, and many more are in clinical studies. There is an excellent need for patenting molecules from natural products as the hit lead molecules are derived, isolated, and synthesized from natural products. However, these naturally occurring products may not be patentable under the law because they come from nature. This review highlights why natural products and compounds are hard to patent, under what patent law criteria we can patent these natural products and compounds, patent procedural guideline sources and why researchers prefer publication rather than a patent. Here, various patent scenarios of natural products and compounds for cancer have been given.

Background: KRAS and BRAF targets are involved in the epidermal growth factor receptor pathway. KRAS and BRAF targets are the most frequent driver mutations in cancer. Objective: The objective of the study was to present the recent developments in the KRAS target and the BRAF target. Methods: KRAS target and BRAF target were analyzed by US patent analysis. All US granted patent documents from January 2002 to November 2021 were retrieved. Results: The results showed both KRAS and BRAF targets to be attractive targets for developing anticancer drugs. The technology of RNA interference has been developed for drug discovery related to the KRAS target. Our study indicates that the structural screening of inhibitors between the KRAS target and the BRAF target should be an inverse option. Conclusion: The chemical structures of inhibitors of BRAF target exhibited a unique classification of C07D405. The inhibitors of BRAF target could be used for the treatment of various cancers. However, the inhibitors of KRAS target did not show this feature. The present study provides new insight into drug discovery involving KRAS and BRAF targets.

Background: The occurrence and progression of cancer are the results of the dysregulation of genetics and epigenetics. Epigenetic regulation can reversibly affect gene transcription activity without changing DNA structure. Covalent modification of histones is crucial in the epigenetic regulation of gene expression. Furthermore, epidermal growth factor receptor (EGFR) significantly affects cell tumorigenesis, proliferation, antitumor drug resistance, etc. Overexpression of EGFR promotes cancer development. Therefore, EGFR-targeted drugs have become the focus of tumor therapy. With the advent of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), EGFR-TKIs resistance, which occurs about half a year to a year, has become an obstacle in cancer treatment. Objective: The objective of this study is to discuss the ways to overcome EGFR-TKIs resistance in a variety of tumors. Methods: The combination therapy of epigenetic drugs and other drugs is used. Results: The combination of the two drugs can overcome the resistance of EGFR-TKIs and prolong the survival of patients. Conclusion: This article depicts the concepts of epigenetics and the mechanism of EGFR-TKIs resistance and then illustrates the relationship between epigenetic mechanisms and EGFR-TKIs resistance. Finally, it discusses the clinical research and the latest patents for using epigenetic drugs to reverse EGFR-TKIs resistance in human cancer. In the future, more novel targets may be discovered for overcoming resistance to EGFR-TKIs, not just on histone deacetylases (HDACs). The dosing course and mode of administration of the combination therapy containing epigenetic drugs need further study. This review provides new ideas for using epigenetic agents to overcome EGFR-TKIs resistance.

Background: Hepatocellular carcinoma (HCC) is one of the most life-threatening malignant diseases. TCTN2 protein participates in tumorigenesis and development. However, whether lncRNA TCTN2 is associated with HCC pathogenesis remains unclear. Methods: The expression of lncRNA, TCTN2, miR-1285-3p, and ARF6 in HCC tissues and cells was detected by a quantitative Real-Time PCR (qRT-PCR) assay. lncRNA TCTN2-specific shRNA was transfected into HCC cells, and a functional investigation was performed. The direct interactions between lncRNA TCTN2 and miR-1285-3p and ARF6 were verified by dualluciferase reporter gene assay. A rescue experiment was performed to confirm the role of miR- 1285-3p/ARF6 in association with lncRNA TCTN2. Results: LncRNA TCTN2 exhibited a high expression in HCC tumor tissues and cell lines. Knockdown of lncRNA TCTN2 suppressed cell proliferation and induced cell cycle arrest and apoptosis through regulating Cyclin D1/p21 and Bax/Bcl-2 signals. Meanwhile, the knockdown of lncRNA TCTN2 inhibited HCC cell migration and invasion through upregulating MMP2/MMP9. Mechanistic investigation revealed that lncRNA TCTN2 upregulated the expression of ARF6 via sponging miR-1285-3p. Rescue experiments indicated that miR-1285-3p inhibitor reversed the antitumor effects of lncRNA TCTN2 and ARF6 knockdown inhibited the progression of HCC. Conclusion: Our results suggested that the knockdown of lncRNA TCTN2 inhibited HCC development by regulating the miR-1285-3p/ARF6 axis, implying that the lncRNA TCTN2 is upregulated in HCC and may serve as a diagnostic biomarker in HCC. Furthermore, it may demonstrate an important value for the clinical treatment of patients with HCC.

Background: Thymic epithelial tumors (TETs) are rare thoracic malignancies with no standard second-line treatment. Tumor angiogenesis is closely associated with the pathogenesis and invasiveness of TETs. Anlotinib is a small-molecule multitarget tyrosine kinase inhibitor (TKI) which inhibits tumor angiogenesis and tumor cell proliferation. Published studies have demonstrated the promising clinical effect of multitarget TKIs sunitinib and lenvatinib in previously treated TETs. However, TKIs have a high incidence of adverse events (AEs). Objective: In this study, we investigated the clinical efficacy and safety of anlotinib in previously treated TET patients. Methods: We collected clinical data of 22 patients from Shandong Cancer Hospital and Institute between October 2018 and March 2022. These patients were diagnosed with advanced TETs and received at least the first-line (1st-line) treatment. We analyzed the clinical effects between anlotinib monotherapy and anlotinib combination therapy in the second-line (2nd-line) or anlotinib treatment in different lines. Results: These 22 patients included 18 cases of thymic carcinoma (TC) and 4 cases of thymoma (T). 68.2% of patients were males, and the median age was 53 years. Fourteen patients (63.6%) received anlotinib monotherapy and 8 patients (36.4%) received anlotinib combination therapy. The objective response rate (ORR) was 9.1% in the overall patients. The median progression-free survival (PFS) in the overall population was 12 months (14 months for T and 9 months for TC), and the median overall survival (OS) was 24 months (survival was not reached for T and was 24 months for TC). The incidence of AEs was 50%, most of them were grades I and II, and the incidence of grades III and IV AEs was 9%. Conclusion: This is the first study reporting the clinical effect of anlotinib in previously treated TETs patients. The survival data indicate that the efficacy of anlotinib is superior to sunitinib and lenvatinib. Our results suggest that anlotinib is a promising treatment option for previously treated TET patients and its toxicity is tolerable. More research and patents are needed in the future to explore better options for the diagnosis and treatment of TETs.

Background: Acute lymphoblastic leukemia with MLL/AF4 rearrangement remains a major hurdle to improving outcomes. Gene network and circRNAs have been found to participate in tumorigenesis, while their roles in leukemia still need to be explored. Recent patents have shown that circRNAs exhibit the markers for the children ALL, although the target and related mechanism remain to be elucidated. Objective: This study aims to explore the possible targets and mechanisms of ALL with MLLAF4 rearrangement. Methods: We first generated a gene network focusing on MLL-AF4 rearrangement. Cell viability was determined with Cell Counting Kit-8 assay. The cell apoptosis was tested by the Annexin V/PI assay. The RNA-protein complexes were analyzed by qRT-PCR, and the pathway proteins were analyzed by western blot. Results: This gene network was associated with biological processes, such as nucleic acid metabolism and immunity, indicating its key role in inflammation. We found that circ_0008012 was upregulated in MLL/AF4 ALL cells and regulated cell proliferation and apoptosis. Further computed simulation and RIP showed that IKKβ was the strongest protein in the NF-ΚB pathway binding with circ_0008012. As a result, possible regulation of circ_0008012 is suggested by binding IKKβ in the IKKα:IKKβ:IKKγ compound, which then phosphorylates IΚB and activates NF- ΚB:p65:p300 compound in cell nucleus, thereby leading to leukemia. Conclusion: We identified a gene network for MLL/AF4 ALL. Moreover, circ_0008012 may be a therapeutic target for this subtype of ALL.

The present disclosure relates to p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of the p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for treating various diseases such as cancer, rheumatoid arthritis, amyotrophic lateral sclerosis, cystic fibrosis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, COVID-19, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI).