Abstract
Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 2 / antagonists & inhibitors
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Cyclin-Dependent Kinase 2 / metabolism
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors
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Cyclin-Dependent Kinase 6 / metabolism
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Dogs
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Female
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Humans
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Injections, Intravenous
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Mice
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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CDK2 protein, human
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CDK4 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6