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Early development of cyclin dependent kinase modulators
1Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Insstitute, 10 center Drive, Building no 10, Room no 6N, Bethesda, MD-20892-5680, USA. kr91w@nih.gov
Abstract:
The protein kinase family presents remarkable opportunities for drug discovery and development targeting mainly to the ATP binding cleft. Cyclin-dependent kinases CDKs control the cell division in by controlling its sub phases. The regulation of CDKs is altered in a number of tumor types, and therefore CDKs are a particularly attractive target group of kinases with reference to proliferative disorders including cancer, but also extending to graft stenosis, and autoimmune disorders. Screening of chemical modulators of CDKs that modulate aberrant CDK activity might be beneficial for cancer therapy by directly inhibiting kinase activity, or influencing cell cycle "checkpoint" function, which is mediated through effects of exogenous cellular regulators of CDK activity. In this regard small molecule modulators such as flavopiridol and UCN-01 are in early clinical trials. Other more selective modulators of CDK function are being actively sought, and initial results with flavopiridol analogs, indirubins, paullones, and purine-based inhibitors will be considered.
Insights
Protein kinases, especially cyclin-dependent kinases (CDKs), are key targets for cancer drug discovery. Modulating CDK activity offers therapeutic potential for various proliferative disorders.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Protein kinases, particularly cyclin-dependent kinases (CDKs), regulate cell division and are frequently dysregulated in various cancers.
- Aberrant CDK activity is implicated in proliferative disorders such as cancer, graft stenosis, and autoimmune diseases, making them attractive therapeutic targets.
Purpose of the Study:
- To explore the potential of small molecule modulators targeting the ATP binding cleft of protein kinases, focusing on CDKs.
- To review current strategies and emerging drug candidates for modulating aberrant CDK activity in cancer therapy.
Main Methods:
- Screening of chemical compounds to identify modulators of CDK activity.
- Review of existing and investigational small molecule inhibitors, including flavopiridol, UCN-01, flavopiridol analogs, indirubins, paullones, and purine-based inhibitors.
Main Results:
- Small molecule modulators can inhibit kinase activity or influence cell cycle checkpoint functions.
- Several classes of CDK inhibitors, including flavopiridol and UCN-01, are in early clinical trials.
Conclusions:
- Targeting protein kinases, especially CDKs, represents a significant opportunity for developing novel therapeutics for cancer and other proliferative diseases.
- The development of selective CDK modulators is crucial for effective cancer therapy and managing related disorders.