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Cyclin Dependent Kinases
Cyclin-dependent kinases (CDKs) partner with regulatory cyclin subunits to govern cell-cycle progression and DNA synthesis, and their dysregulation is a hallmark of human cancers. CDK2 drives the G1/S transition and is an attractive target for suppressing cancer-cell growth, though no CDK2-directed drug has yet reached the market.
CDK4 and CDK6 partner with cyclin D to control the G1-phase checkpoint via retinoblastoma (Rb) phosphorylation and are validated targets in hormone-receptor-positive breast cancer, where mutation of the estrogen receptor (ESR1/ERα) frequently drives resistance to endocrine therapy.
Our approach
Drawing on Protein Data Bank structures for CDK2, CDK4/6 and ESR1 with their bound ligands, we apply molecular docking, drug-repurposing screens, molecular dynamics and free-energy calculations to optimize inhibitors of these targets individually or in dual CDK/ESR1 combinations relevant to breast cancer.