Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
Sandeep Rana1, Jayapal Reddy Mallareddy2, Sarbjit Singh2
1Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Abstract:
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 "neo-substrate" 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.
Insights
Cyclin-dependent kinase (CDK) inhibitors face challenges in selectivity and toxicity. Proteolysis Targeting Chimeras (PROTACs) and molecular glues offer new ways to degrade CDK proteins, potentially improving cancer therapy.
Area of Science:
- Molecular Biology
- Oncology
- Drug Discovery
Background:
- Cyclin-dependent kinases (CDKs) are crucial regulators of transcription, mRNA processing, and cell cycle, making them key targets in cancer therapy.
- Palbociclib, the first FDA-approved CDK inhibitor, targets CDK4/6 but lacks selectivity, leading to dose-limiting toxicities.
- Over 30 clinical trials are investigating CDK inhibitors, highlighting the ongoing need for improved therapeutic strategies.
Purpose of the Study:
- To review emerging therapeutic modalities, specifically Proteolysis Targeting Chimeras (PROTACs) and molecular glues, for targeting CDKs.
- To discuss the potential of these novel approaches to overcome the limitations of traditional small molecule CDK inhibitors.
Main Methods:
- Review of preclinical and clinical data on CDK inhibitors, PROTACs, and molecular glues.
- Explanation of the mechanisms of action for PROTACs (heterobifunctional molecules forming ternary complexes) and molecular glues (neo-substrate conversion for E3 ligases).
- Analysis of selectivity and efficacy profiles compared to traditional small molecule inhibitors.
Main Results:
- PROTACs and molecular glues leverage the cell's natural protein degradation machinery to eliminate target proteins.
- Preclinical studies indicate that PROTACs targeting CDKs demonstrate enhanced selectivity compared to conventional inhibitors.
- The efficacy of PROTACs and molecular glues is dependent on ternary complex formation rather than solely on molecular dose.
Conclusions:
- PROTACs and molecular glues represent promising alternative therapeutic modalities for modulating CDK function in cancer.
- These approaches offer potential advantages in terms of selectivity and overcoming resistance mechanisms associated with traditional inhibitors.
- Further investigation into PROTACs and molecular glues is warranted to advance their clinical application in oncology.
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