Discovery of novel and selective CDK4/6 inhibitors by pharmacophore and structure-based virtual screening

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Pharmacology

Background:

• Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell cycle progression, making them key targets for cancer therapy.
• Inhibiting CDK4/6 offers a promising strategy for treating various cancers, including multiple myeloma.

Purpose of the Study:

• To discover novel inhibitors of CDK4/6 using computational screening methods.
• To optimize lead compounds for enhanced potency and selectivity against CDK4/6.
• To evaluate the therapeutic potential of identified inhibitors in preclinical models.

Main Methods:

• Screening of chemical databases (Specs and in-house library) using pharmacophore modeling and LibDock protocol.
• Clustering of retrieved hits into 100 distinct clusters for analysis.
• In vitro evaluation of CDK4/6 inhibitory activity using enzymatic assays.
• Iterative chemical optimization of the most promising hit compound.

Main Results:

• Identification of a novel CDK4/6 inhibitor, designated compound 10, through integrated computational approaches.
• Chemical optimization resulted in compound 18, a highly selective and potent CDK4/6 inhibitor.
• Compound 18 demonstrated significant potential for the treatment of multiple myeloma.

Conclusions:

• The combined use of pharmacophore modeling and molecular docking is an effective strategy for discovering novel kinase inhibitors.
• Compound 18 represents a promising therapeutic candidate for multiple myeloma due to its high selectivity and potency.
• Further investigation into compound 18's efficacy and safety is warranted for clinical development.