A patent and literature review of CDK12 inhibitors

ABSTRACT

Introduction

Cyclin-dependent kinase 12 (CDK12) belongs to the CDK family of serine/threonine protein kinases and is associated with cyclin K to exert its biological functions, including regulating gene transcription, mRNA processing, and translation. Increasing evidences demonstrate the importance of CDK12 in various human cancers, illustrating its potential as both biomarker and therapeutic target. In addition, CDK12 is also a promising target for the treatment of myotonic dystrophy type 1. Efforts have been taken to discover small molecule inhibitors to validate this important therapeutic target.

Areas covered

This review covers the patented CDK12 inhibitors from 2016 to present, as well as these from peer-reviewed literature. It provides the reader an update of the discovery strategies, chemical structures, and molecular profiling of all available CDK12 inhibitors.

Expert opinion

CDK12 inhibitors with various mechanism of actions have been discovered, and it is a great set of tools to evaluate the therapeutic potential of CDK12 in different disease models. CDK12 inhibitors have shown promising results in myotonic dystrophy type 1 mouse model and several preclinical cancer models either as single agent or combination with other anti-cancer agents. Its therapeutic value awaits more rigorous preclinical testing and further clinical investigation.

KEYWORDS:

• Anti-cancer agents
• CDK12/cyclin K
• DNA damage response
• myotonic dystrophy type 1
• PROTAC
• transcription
• molecular-glue degrader

Article highlights

• CDK12 is a promising therapeutic target for the treatment of several types of cancer and myotonic dystrophy type 1.

• CDK12 inhibitors have shown promising results in preclinical models of cancers and myotonic dystrophy type 1.

• Various CDK12 small molecule inhibitors with different mechanism of actions have been identified, including the inhibition of its kinase activity and the degradation of CDK12 or its activating partner cyclin K.

• This review updates the discovery and chemical structures of all CDK12 small molecule inhibitors.

Declaration of interests

The 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 royalties.

Reviewer disclosures

One reviewer is listed as an investor on WO2019217421 described in this review article. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (grant 82104001 to H.S, 32170821, 31771589, 91853108 to K.Y, and 32101034 to F.C), Department of Science & Technology of Hunan Province (grant 2021JJ41015 to H.S, 2021JJ10054, 2019SK1012, 2018DK2015, 2017RS3013, 2017XK2011 to K.Y, the innovative team program 2019RS1010, and 2021JJ41049 to C.Y), Central South University (2018CX032 to K.Y, and the innovation-driven team project 2020CX016).