Allosteric CDC37 Inhibitor Disrupts Chaperone Complex to Block CDK4/6 Maturation
Lixiao Zhang1,2, Wei Liu1,2, Zhen Zheng3,4
1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
Angewandte Chemie (International Ed. in English)
|November 25, 2024
Summary
A new small molecule, DDO-6079, inhibits CDC37 (cell division cycle 37) and disrupts cancer-promoting chaperone complexes. This approach selectively targets oncogenic kinases, offering a novel strategy for cancer therapy.
Area of Science:
- Molecular Biology
- Oncology
- Drug Discovery
Background:
- Cell division cycle 37 (CDC37) is a molecular chaperone and cochaperone of heat shock protein 90 (HSP90).
- CDC37 stabilizes oncogenic kinases via the HSP90-CDC37-kinase complex, crucial for cancer cell survival.
- Targeting CDC37 offers a strategy to selectively inhibit oncogenic kinase maturation.
Purpose of the Study:
- To develop and characterize a novel small-molecule inhibitor of CDC37.
- To investigate the mechanism of action of the inhibitor in disrupting chaperone complexes.
- To evaluate the therapeutic potential of the inhibitor against cancer.
Main Methods:
- Development of a small-molecule CDC37 inhibitor, DDO-6079.
- Assays to assess inhibition of HSP90-CDC37 and CDC37-CDK4/6 chaperone complexes.
- Evaluation of oncogenic kinase maturation and heat shock response (HSR) evasion.
- Assessment of CDK6 thermostability and drug resistance reversal in colorectal cancer cells.
- In vivo efficacy studies.
Main Results:
- DDO-6079 simultaneously inhibits HSP90-CDC37 and CDC37-CDK4/6 complexes by binding to CDC37.
- DDO-6079 selectively inhibits oncogenic kinase maturation and evasion of HSR.
- The inhibitor decreases CDK6 thermostability and reverses palbociclib resistance in colorectal cancer.
- DDO-6079 demonstrates efficacy in vivo.
Conclusions:
- DDO-6079 is a first-in-class small molecule inhibitor of CDC37.
- Disruption of the HSP90-CDC37-kinase chaperone complex is a viable therapeutic strategy.
- DDO-6079 represents a promising new approach for blocking kinase maturation in cancer treatment.
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