Journal
FUTURE MEDICINAL CHEMISTRY
Volume 12, Issue 12, Pages 1121-1136Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc-2020-0011
Keywords
CDK4; 6 inhibitors; hit identification; molecular docking; multiple myeloma; pharmacophore
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Funding
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZRC07]
- 111 Project [B16046]
- 'Double First-Class' University Project [CPU2018GF04]
- Jiangsu Key Laboratory of Drug Design and Optimization [DORC201801]
- 65th China Postdoctoral Science Foundation [2019M652030]
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Aim: CDK4 and 6 are the key initiators in the transition from G1 to S phase in the cell cycle; thus, inhibition of CDK4/6 is a promising strategy for cancer treatment. Materials & methods: The Specs database and an in-house library were screened via the pharmacophore model and LibDock protocol and then the retrieved hits were clustered into 100 clusters. The CDK4/6 inhibitory activity of selected compounds was evaluated by CDK enzymatic assays, followed by chemical optimization of the top hit compound. Results & conclusion: The integration of pharmacophores and molecular docking offered us an effective method to discover the novel CDK4/6 inhibitor 10 and further chemical optimization led to the highly selective and potent CDK4/6 inhibitor 18, which exhibited potential for the treatment of multiple myeloma. Graphical abstract
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