Inhibitors and PROTACs of CDK2: challenges and opportunities
Yangjie Zeng1, Xiaodong Ren1, Pengyao Jin1
1Medical College, Guizhou University, Guiyang, China.
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.
Insights
Cyclin-dependent kinase 2 (CDK2) inhibitors show promise for cancer treatment by targeting uncontrolled cell proliferation. However, challenges in selectivity and toxicity necessitate further research for effective clinical application.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Overexpression of CDK2-cyclin A/E complexes disrupts cell cycle regulation, driving cancer cell proliferation.
- CDK2 is a validated therapeutic target for cancer treatment.
- Structural insights into CDK2 catalytic and allosteric sites enable rational drug design.
Purpose of the Study:
- To review recent clinical and preclinical CDK2 inhibitors.
- To discuss the development of allosteric CDK2 inhibitors and PROTACs.
- To summarize design strategies, SAR, and biological assessments.
Main Methods:
- Review of clinical trial data for CDK2 inhibitors.
- Analysis of preclinical CDK2 inhibitor design and discovery.
- Summarization of allosteric inhibitor and PROTAC development strategies.
- Evaluation of structure-activity relationships and biological assessments.
Main Results:
- Several CDK2 inhibitors have entered clinical trials.
- Promising preclinical CDK2 inhibitors, allosteric inhibitors, and PROTACs have been developed.
- Current inhibitors face challenges with selectivity and toxicity.
Conclusions:
- Optimization of selectivity, potency, and pharmacokinetics is crucial for CDK2 inhibitors and PROTACs.
- Combination therapies and multi-target inhibitors offer future therapeutic potential.
- Further research is needed to overcome clinical limitations and advance cancer treatment.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:39Positive Regulator Molecules
00:50Anaphase Promoting Complex
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:28The Cell Cycle Control System
Cyclins and cyclin-dependent kinases (Cdks) are the primary cell cycle regulators and...