A patent review of small molecule CDK4/6 inhibitors in the treatment of cancer: 2020-present.

INTRODUCTION: Cyclin-dependent protein kinase 4/6 (CDK4/6) is a class of serine/threonine protein kinases that plays a key role in the regulation of the cell cycle. CDK4/6 is highly expressed in cancers such as breast cancer, melanoma, and non-small cell lung cancer (NSCLC). Currently, a variety of CDK4/6 inhibitors have been developed, aiming to develop effective inhibitors to solve CDK4/6 resistance and toxicity. AREAS COVERED: This article searches patents through Espacenet and reviews the development of widely studied CDK inhibitors and FDA-approved CDK4/6 inhibitors, as well as the latest progress of patented inhibitors with good inhibitory activity against CDK4/6 from 2020 to now. EXPERT OPINION: CDK4/6 is highly expressed in many tumors and has become an important anti-tumor target. Among the patents from 2020 to the present, many inhibitors have good kinase inhibitory effects on CDK4/6 and also show great development potential in anti-tumor. However, there is still an urgent need to develop novel CDK4/6 inhibitors that address challenges such as drug resistance, toxicity, and selectivity.

Insights into the Overcoming EGFRDel19/T790M/C797S Mutation: A Perspective on the 2-Aryl-4-aminothienopyrimidine Backbone.

The epithelial growth factor receptor (EGFR) signaling pathway has been proposed to benefit non-small cell lung cancer (NSCLC) treatment. In this manuscript, we investigated the modification of 2-aryl-4-aminoquinazoline, the classical backbone of the fourth-generation EGFR inhibitors, in addition to obtaining a series of novel 2-aryl-4-aminothienopyrimidine derivatives (A1~A45), we also gained further understanding of the modification of this framework. Derivatives were tested for cytotoxicity against cancer cell lines (cervical cancer cell line Hela, lung cancer cell lines A549, H1975, and PC-9, Ba/F3-EGFRDel19/T790M/C797S cells, and human normal hepatocytes LO2) as well as for the derivative's inhibitory activity against EGFRWT, EGFRL858R/T790M, and EGFRDel19/T790M/C797S kinase inhibitory activities. The results showed that most of the target compounds showed moderate to excellent activity against one or more cancer cell lines. Among them, the antitumor activity (IC50) of the most promising A9 against A549 and H1975 cell lines was 0.77±0.08 µM, 6.90±0.83 µM, respectively. At concentration of 10 µM, A9 can be employed as the fourth-generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFRDel19/T790M/C797S cells and kinase by 98.90 % and 85.88 %, respectively. Moreover, the tumor-bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo, with the tumor inhibition rate (TIR) of 55.92 %, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.

Novel bioactive 2-phenyl-4-aminopyrimidine derivatives as EGFRDel19/T790M/C797S inhibitors for the treatment of non-small cell lung cancer.

Overexpression of the epidermal growth factor receptor (EGFR) has been implicated in the development of non-small-cell lung cancer (NSCLC). Thus, EGFR is an effective drug target for the treatment of NSCLC, and developing fourth-generation EGFR inhibitors to overcome the resistance mediated by T790M/C797S mutations are currently under investigation. In this study, based on the binding model between Angew2017-7634-1 and EGFRT790M/C797S , several series of 2-phenyl-4-aminopyrimidine derivatives were designed and synthesized. The bioactivity of these compounds was evaluated and it is suggested that compound A23 could effectively inhibit the proliferation of Ba/F3-EGFRDel19/T790M/C797S and H1975-EGFRL858R/T790M cells, with an IC50 of 0.22 ± 0.07 and 0.52 ± 0.03 µM, respectively. Meanwhile, the kinase activity of A23 against EGFRL858R/T790M and EGFRDel19/T790M/C797S was also evaluated, with an IC50 of 0.33 and 0.133 µM, respectively. Moreover, compound A23 was further evaluated in the H1975 xenograft models with significant in vivo tumor growth inhibitions of 25.5%, which means that A23 could effectively inhibit the growth of tumor cells and promote the death of tumor cells. As a result, A23 could be identified as a novel potential EGFRDel19/T790M/C797S inhibitor.

Association of dual electronic cigarettes and marijuana use with sleep duration among adults from the United States, NHANES 2015-2018.

Electronic cigarette (e-cigarette) use is becoming more widespread, and studies show that they are not absolutely harmless. To investigate the association between the dual use of e-cigarettes and marijuana with sleep duration among adults in the United States, this cross-sectional study used data from 6,573 participants aged 18-64 years from 2015 to 2018 from the National Health and Nutrition Examination Survey database. Chi-square tests and analysis of variance were used for bivariate analyses of binary and continuous variables, respectively. Multinomial logistic regression models were used for univariate and multivariate analyses of e-cigarette use, marijuana use, and sleep duration. Sensitivity analyses were conducted in populations with dual e-cigarette and traditional cigarette use and dual marijuana and traditional cigarette use. People who concurrently use e-cigarettes and marijuana had higher odds of not having the recommended sleep duration than neither users (short sleep duration: odds ratio [OR], 2.34; 95% confidence interval [CI], 1.19-4.61; P = 0.014; long sleep duration: OR, 2.09; 95% CI, 1.53-2.87; P < 0.001) and a shorter sleep duration than e-cigarette only users (OR, 4.24; 95% CI, 1.75-4.60; P < 0.001). Concurrent traditional cigarette and marijuana users had higher odds of long sleep duration than neither users (OR, 1.98; 95% CI, 1.21-3.24; P = 0.0065). Almost half of the people who concurrently use e-cigarettes and marijuana had both short and long sleep durations compared to neither users and short sleep duration compared to e-cigarette only users. Longitudinal randomized controlled trials are needed to explore the joint effect of dual tobacco use on sleep health.

Pyrrole-based EGFR inhibitors for the treatment of NCSLC: Binding modes and SARs investigations.

The treatment of advanced non-small cell lung cancer (NSCLC) has made substantial progress due to the rapid development of small molecule targeted therapy, with dramatically prolonged survival. As an effective drug for the treatment of NSCLC, epidermal growth factor receptor (EGFR) inhibitors are currently experiencing issues like severe adverse events and drug resistance. It is urgent to develop novel types of EGFR inhibitors to overcome the abovementioned limitations. Pyrrole always works well as a probe for the creation of novel medication candidates for hard-to-treat conditions like lung cancer. Although the design, synthesis, and biological assays of pyrrole derivatives have been reported, their inhibitory actions against the receptor tyrosine kinase (RTK) EGFR have not been in-depthly studied. This review highlights the small molecule EGFR inhibitors containing pyrrole heterocyclic pharmacophores in recent years, and the research on their mechanism, biological activity, and structure-activity relationship (SAR).