Inhibitors and PROTACs of CDK2: challenges and opportunities

ABSTRACT

Introduction

Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors.

Area covered

This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments.

Expert opinion

Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.

KEYWORDS:

• CDK2
• cancer
• inhibitor
• PROTAC
• SAR

Article highlights

• CDK2 maintains an ‘in’ conformation of the DFG motif in its inactive state, which contrasts with the canonical ‘out’ state observed in most kinases.

• The most recent CDK2 inhibitors that have entered clinical trials, along with the most promising selective CDK2 inhibitors developed within the past five years, have been reviewed.

• Unprecedentedly high-affinity CDK2 allosteric inhibitors have been identified.

• Challenges and strategies in the design of type 1, type 2, allosteric, and covalent selective CDK2 inhibitors are presented.

• PROTACs, as a novel targeting approach for CDK2, possess the potential for superior selectivity over traditional inhibitors through the use of the target-binding arm.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

One reviewer declares that they are a former employee and consultant for Evotec who has their own drug discovery consultancy company. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by Guizhou Provincial Basic Research Program (Natural Science) [No. Qiankehe-Basic-ZK[2021]-general 556], the Guizhou University Talent Introduction Research Project [No. Guidarenjihezi (2020) number 76], the Guizhou Provincial Basic Research Program (Natural Science) [No. Qiankehe-Basic-ZK[2021]-general 405], the Health Commission of Guizhou Province [Grant Number: gzwkj2022-004], the National Natural Science Foundation of China (82160222), Guizhou Provincial Basic Research Program (Natural Science) [No. Qiankehe-Basic-ZK[2022]-general 261], Guizhou Provincial People’s Hospital National Science Foundation (GPPH-NSFC-2021-14).