Rana Sandeep, Mallareddy Jayapal Reddy, Singh Sarbjit, Boghean Lidia, Natarajan Amarnath
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Cancers (Basel). 2021 Nov 2;13(21):5506. doi: 10.3390/cancers13215506.
The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule-protein interactions. On the other hand, Molecular glues function by converting the target protein into a "" for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities.
细胞周期蛋白依赖性激酶（CDK）家族蛋白在转录、mRNA加工和细胞周期调控中发挥着重要作用，使其成为有吸引力的癌症靶点。哌柏西利是首个获美国食品药品监督管理局（FDA）批准的CDK抑制剂，它非选择性地靶向CDK4和CDK6的ATP结合位点。在本综述中，我们将简要梳理那些属于30多项正在进行的临床试验或正在招募患者的CDK抑制剂。CDK之间缺乏选择性以及剂量限制性毒性是与CDK抑制剂开发相关的主要挑战。靶向蛋白降解嵌合体（PROTAC）和分子胶已成为靶向蛋白质的替代治疗方式。PROTAC和分子胶利用细胞内蛋白质降解机制来破坏靶蛋白。PROTAC是异双功能分子，通过形成两种不同的小分子-蛋白质相互作用与靶蛋白和E3连接酶形成三元复合物。另一方面，分子胶通过将靶蛋白转化为E3连接酶的“诱饵”来发挥作用。与小分子抑制剂不同，针对CDK的PROTAC的临床前研究已显示出改善的CDK选择性。此外，PROTAC和分子胶的疗效并不取决于这些分子实体的剂量，而是取决于三元复合物的形成。在此，我们概述了作为新兴治疗方式调节CDK功能的PROTAC和分子胶。
