CDK4/6 inhibitors: a brief overview and prospective research directions
Tenzin Adon1, Dhivya Shanmugarajan1, Honnavalli Yogish Kumar1
1Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagar Mysuru-570015 Karnataka India yogigcp@gmail.com +919726447802.
Abstract:
The discovery of cyclin-dependent kinases (CDK) and their mechanism in regulating the cell cycle process was considered a game-changer in cancer therapy. Cell cycle arrest and apoptosis were both triggered by their inhibition. The CDK4/6 complex acts as a checkpoint during the cell cycle transition from cell growth (G1) to DNA synthesis (S) phase and its deregulation or overexpression induces abnormal cell proliferation and cancer development. Consequently, targeting CDK4/6 has been proposed as a paradigm shift in the anticancer approach. The design and development of effective CDK4/6 inhibitors are increasingly becoming a promising cancer therapy evident with approved drugs such as palbociclib, ribociclib, and abemaciclib, etc. In this article, we explore the biological importance of CDK4/6 in cancer therapy, the development of resistance to monotherapy, and a short overview of PROTAC (Proteolysis Targeting Chimera), a unique and pioneering technique for degrading CDK4/6 enzymes. Overall, our prime focus is to discuss novel CDK4/6 inhibitors with diverse chemical classes and their correlation with computational studies.
Insights
Targeting cyclin-dependent kinases 4/6 (CDK4/6) offers a promising cancer therapy approach by halting cell cycle progression. This review explores novel CDK4/6 inhibitors, resistance mechanisms, and innovative degradation techniques like PROTAC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDK) regulate the cell cycle, and their inhibition triggers cell cycle arrest and apoptosis.
- CDK4/6 complexes are crucial checkpoints in the G1 to S phase transition; deregulation drives cancer.
- Targeting CDK4/6 represents a significant advancement in cancer treatment strategies.
Purpose of the Study:
- To review the biological significance of CDK4/6 in cancer therapy.
- To discuss the emergence of resistance to CDK4/6 monotherapy.
- To provide an overview of Proteolysis Targeting Chimeras (PROTAC) for CDK4/6 degradation.
Main Methods:
- Exploration of novel CDK4/6 inhibitors across diverse chemical classes.
- Analysis of the correlation between novel inhibitors and computational studies.
- Review of existing literature on CDK4/6 function, inhibition, and resistance.
Main Results:
- CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib are approved cancer therapies.
- Understanding resistance mechanisms is crucial for optimizing CDK4/6-targeted treatments.
- PROTAC technology offers a novel approach for enzyme degradation.
Conclusions:
- Novel CDK4/6 inhibitors with varied chemical structures show therapeutic potential.
- Computational studies aid in the design and understanding of CDK4/6 inhibitors.
- Further research into resistance and novel degradation strategies like PROTAC is warranted for advancing cancer therapy.
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