A patent review of selective CDK9 inhibitors in treating cancer

ABSTRACTIntroduction The dysregulation of CDK9 protein is greatly related to the proliferation and differentiation of various cancers due to its key role in the regulation of RNA transcription. Moreover, CDK9 inhibition can markedly downregulate the anti-apoptotic protein Mcl-1 which is essential for the survival of tumors. Thus, targeting CDK9 is considered to be a promising strategy for antitumor drug development, and the development of selective CDK9 inhibitors has gained increasing attention.Areas covered This review focuses on the development of selective CDK9 inhibitors reported in patent publications during the period 2020–2022, which were searched from SciFinder and Cortellis Drug Discovery Intelligence.Expert opinion Given that pan-CDK9 inhibitors may lead to serious side effects due to poor selectivity, the investigation of selective CDK9 inhibitors has attracted widespread attention. CDK9 inhibitors make some advance in treating solid tumors and possess the therapeutic potential in EGFR-mutant lung cancer. CDK9 inhibitors with short half-life and intravenous administration might result in transient target engagement and contribute to a better safety profile in vivo. However, more efforts are urgently needed to accelerate the development of CDK9 inhibitors, including the research on new binding modes between ligand and receptor or new protein binding sites.KEYWORDS: CancerCDK9inhibitorsMcl-1transient inhibition Article highlights The dysregulation of CDK9 is strongly associated with the development of various cancers, including hematologic and solid tumors.CDK9 inhibition can regulate directly Mcl-1 protein levels and own the potential to overcome drug resistance in the treatment of NSCLC.Patents regarding selective CDK9 inhibitors (2020-2022) are collected and discussed.CDK9 transient inhibition can also achieve potent antitumor activity in vivo, and has attracted extensive attention from researchers.More efforts are still vitally needed to perform mechanistic research to accelerate the development of CDK9 inhibitors.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royaltiesReviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contributions statementT Wu, X Wu, Y Xu are responsible for writing the whole manuscript. Z Li and J Bian are in charge of checking and revision. R Chen and J Wang contribute much work to make figures.Additional informationFundingThis paper was funded by the National Natural Science Foundation of China (no. 81872746, 81703347 and 82104030), the National Natural Science Foundation of Jiangsu Province of China (no. BK20170743, BK20171393 and BK20210422), the State Key Laboratory of Drug Research (SIMM1903KF-03), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18 0770).