Recent patents on anti-cancer drug discovery最新文献

The use of antibody-drug conjugates is expected to transform the management of human malignancy. Antibody-drug conjugates for cancer treatment are designed to deliver anticancer drugs to tumor cells. The main components of such conjugates are a monoclonal antibody that binds to a tumor antigen, an anticancer drug to inhibit tumor cell growth and a linker that serves to conjugate the antibody and drug. The antibody-drug conjugates developed and approved for breast cancer treatment are ado-trastuzumab emtansine, (fam)-trastuzumab deruxtecan-nxki and sacituzumab govitecan. The mechanisms of action, clinical uses and toxic effects of these antibody-drug conjugates are discussed.

Background: In recent years, targeted therapy combined with traditional chemoradiotherapy and surgery has brought new opportunities for cancer treatment. However, the complex characteristics of cancer, such as heterogeneity and diversity, limit the clinical success of targeted drugs. Discovering of new cancer targets and deepening the understanding of their functional mechanisms will bring additional promising application prospects for the research and development of personalized cancer-targeted drugs.

Objectives: This study aimed to summarize the role of the Rho GTPase activating protein 9 (ARHGAP9) gene in tumorigenesis and development to discover therapeutic targets for cancer in the future.

Methods: For this review, we collected patents from the databases of Espacenet and WIPO and articles from PubMed that were related to the ARHGAP9 gene.

Results: Genetic/epigenetic variations and abnormal expression of the ARHGAP9 gene are closely associated with a variety of diseases, including cancer. ARHGAP9 can inactivate Rho GTPases by hydrolyzing GTP into GDP and regulate cancer cellular events, including proliferation, differentiation, apoptosis, migration and invasion, by inhibiting JNK/ERK/p38 and PI3K/AKT signaling pathways. In addition to reviewing these mechanisms, we assessed various patents on ARHGAP9 to determine whether ARHGAP9 might be used as a predictive biomarker for diagnosis/prognosis evaluation and a druggable target for cancer treatment.

Conclusion: In this review, the current knowledge of ARHGAP9 in cancer is summarized with an emphasis on its molecular function, regulatory mechanism and disease implications. Its characterization is crucial to understanding its important roles during different stages of cancer progression and therapy as a predictive biomarker and/or target.

Background: Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine- derived Nitrosamines (NDNs).

Methods: A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis.

Results: Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade, promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR.

Conclusion: Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.

Background: Breast cancer is the most frequently diagnosed type of cancer in women, accounting for 2.1 million cases, and stands as the fifth leading cause of death. Several treatment strategies are available, such as surgical resection, radiation, hormonal therapy, and conventional chemotherapy; however, these are associated with severe adverse effects in the patients.

Objectives: This review aims to summarize the different studies (in vitro, in vivo, and new patents) concerning the therapeutic potential of plant polyphenolics in the management of breast cancer, published in the period from January 2016 to January 2021. Moreover, this review will focus on the underlying mechanisms of action and molecular characteristics of these compounds.

Methods: The data of this review were collected from different scientific databases, such as Pub- Med, Science Direct, Google Scholarship, SciFinder, and Egyptian Knowledge Bank (EKB).

Results: During the period 2016-2021, in the in vitro studies, investigation on 52 compounds of polyphenolic nature with promising anti-breast cancer activity has been conducted, while 14 compounds have been reported via in vivo studies. Besides, about 15 compounds have been registered as patent drugs. Different mechanisms of action and molecular targets have been reported, providing a clarified basis and precise reflection of the anticancer properties of these compounds against breast cancer.

Conclusion: Polyphenolics represent a comprehensive source of anticancer lead compounds against the progression of breast cancer invasion and metastasis.

Background: The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopathological features and genomics.

Methods: We identified hypoxia-related differentially expressed genes (DEGs) between OC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression (GTEx). LASSO Cox regression analysis was applied for building a prognostic model in the TCGA-GTEx cohorts, and its predictive value was validated in the GEO-OC cohort. Functional enrichment analysis was performed to investigate the underlying mechanisms. By constructing a hypoxia model of the SKOV3 cell line and applying qRT-PCR, we investigated the relationship between hypoxia with two novel genes in the prognostic model (ISG20 and ANGPTL4).

Results: Twelve prognostic hypoxia-related DEGs were identified, and nine of them were selected to establish a prognostic model. OC patients were stratified into two risk groups, and the high-risk group showed reduced survival time compared to the low-risk group upon survival analysis. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent risk factor for overall survival. The biological function of the identified prognostic hypoxia-related gene signature was involved in immune cell infiltration. Low expression of ISG20 was observed in the CoCl₂-mimicked hypoxic SKOV3 cell line and negatively correlated with HIF-1α.

Conclusion: Our findings showed that this hypoxia-related gene signature could serve as a satisfactory prognostic classifier for OC and will be beneficial to the research and development of targeted therapeutic strategies.

Background: Finding novel antitumor reagents from naturally occurring alkaloids is a widely accepted strategy. Evodiamine, a tryptamine indole alkaloid isolated from Evodia rutaecarpa, has a wide range of biological activities, such as anti-tumor, anti-inflammation, and anti-bacteria. Hence, research on the structural modification of evodiamine will facilitate the discovery of new antitumor drugs.

Objective: The recent advances in the synthesis of evodiamine, and studies on the drug design, biological activities, and structure-activity-relationships of its derivatives, published in patents and primary literature, are reviewed in this paper.

Methods: The literature, including patents and follow-up research papers from 2015 to 2020, related to evodiamine is searched in the Scifinder, PubMed, Espacenet, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The keywords are evodiamine, synthesis, modification, anticancer, mechanism.

Results: The synthesis of evodiamine is summarized. Then, structural modifications of evodiamine are described, and the possible modes of action are discussed.

Conclusion: Evodiamine has a 6/5/6/6/6 ring system, and the structural modifications are focused on rings A, D, E, C5, N-13, and N-14. Some compounds show promising anticancer potentials and warrant further study.

Background: Therapeutic resistance is a frequent problem of cancer treatment and a leading cause of mortality in patients with metastatic colorectal cancer (CRC). Recent insight into the mechanisms that confer multidrug resistance has elucidated that the ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) assists cancer cells in escaping therapeutic stress caused by toxic chemotherapy. Therefore, it is necessary to develop ABCG2 inhibitors.

Objectives: In the present study, we investigated the inhibitory effect of KU55933 on ABCG2 in CRC.

Methods: The cytotoxicity assay and drug accumulation assay were used to examine the inhibitory effect of KU55933 on ABCG2. The protein expressions were detected by Western blot assay. The docking assay was performed to predict the binding site and intermolecular interactions between KU55933 and ABCG2.

Results: KU55933 was more potent than the known ABCG2 inhibitor fumitremorgin C to enhance the sensitivity of mitoxantrone and doxorubicin and the intracellular accumulation of mitoxantrone, doxorubicin and rhodamine 123 inside CRC cells with ABCG2 overexpression. Moreover, KU55933 did not affect the protein level of ABCG2. Furthermore, the docking data showed that KU55933 was tightly located in the drug-binding pocket of ABCG2.

Conclusion: In summary, our data presented that KU55933 could effectively inhibit the drug pump activity of ABCG2 in colorectal cancer, which is further supported by the predicted model that showed the hydrophobic interactions of KU55933 within the drug-binding pocket of ABCG2. KU55933 can potently inhibit the activity of ABCG2 in CRC.

Background: The incidence of melanoma has been increasing over the last 30 years. The most common treatments, such as surgery, chemotherapy, and radiotherapy, frequently cause serious damage to the body. It is therefore critical to develop a new therapeutic strategy for the treatment of melanoma.

Objectives: This research aims to evaluate the anti-tumor effect of Neochamaejasmine A (NCA) on B16F10 melanoma cells and the underlying molecular mechanisms.

Methods: The CCK-8 kit was utilized to assay the influence of NCA on the vitality of B16F10 cells. Modifications in B16F10 cells morphology were observed using a phase-contrast microscope. Apoptosis of B16F10 melanoma cells was assessed by Hoechst 33258, Annexin V and propidium iodide staining. Cell cycle was detected using a commercial kit by flow cytometry. The mRNA and protein expression levels associated with apoptosis and cell cycle arrest were detected by RT-PCR and Western blot. The expression level of pathway proteins was assessed using Western blot.

Results: It was found that the proliferation of B16F10 cells was inhibited by NCA in concentration- and time-dependent manners. NCA promoted apoptosis by halting the cell cycle at the G2/M phase. After treatment with NCA, cell apoptosis was confirmed by Hoechst 33258 staining. NCA triggered the cell cycle to seize at the G2/M stage by downregulating cyclin B1 and cyclin-dependent kinase 2 (CDC2) expression. Moreover, the mRNA and protein expression of cleaved caspase- 9 and Bcl-2-associated X-protein (Bax) were increased, whereas there was a decline in the expression of B-cell lymphoma 2 (Bcl-2). The p-p38/p38 and phosphorylated c-Jun N-terminal kinase (p-JNK/JNK) ratio were also elevated by NCA. The apoptosis and G2/M cell cycle arrest were inhibited in cells co-treated with the p38 inhibitor SB203580 and JNK inhibitor SP600125. The expression of apoptosis-related proteins Bax was decreased, and Bcl-2 was increased.

Conclusion: The findings of this study showed that NCA could induce apoptosis and cell cycle arrest in B16F10 melanoma cells by activating JNK and p38 MAPK signaling pathway.