9pe8
CDK6 to CDK4 active site surrogate in complex with PF-07220060
Structural highlights
FunctionCDK6_HUMAN Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during interphase at G1 to form a pRB/RB1 kinase and controls the entrance into the cell cycle. Involved in initiation and maintenance of cell cycle exit during cell differentiation; prevents cell proliferation and regulates negatively cell differentiation, but is required for the proliferation of specific cell types (e.g. erythroid and hematopoietic cells). Essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Required during thymocyte development. Promotes the production of newborn neurons, probably by modulating G1 length. Promotes, at least in astrocytes, changes in patterns of gene expression, changes in the actin cytoskeleton including loss of stress fibers, and enhanced motility during cell differentiation. Prevents myeloid differentiation by interfering with RUNX1 and reducing its transcription transactivation activity, but promotes proliferation of normal myeloid progenitors. Delays senescence. Promotes the proliferation of beta-cells in pancreatic islets of Langerhans.[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedInhibitors of cyclin-dependent kinases 4 and 6 have been shown to be clinically effective for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced, or metastatic breast cancer. These agents, however, often show neutropenia, likely due to the role of CDK6 in hematopoiesis. Herein described is the discovery of a series of aminopyrimidine-based selective CDK4 inhibitors. Central to our strategy were efficiency-based optimization (LipE and LipMetE), structure-based drug design, and molecular dynamics simulation. The culmination of these efforts resulted in the discovery of PF-07220060 (atirmociclib), which possessed high potency and levels of selectivity for CDK4 over CDK6 that translated to minimal impact on neutrophils while driving efficacy in a mouse ZR75-1 xenograft model. Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor.,Gallego GM, Palmer C, Orr S, Bernier L, Chen P, Cho-Schultz S, Deal JG, Dress K, Edwards M, Jalaie M, Johnson E, Kania R, Kath JC, Lafontaine J, Ninkovic S, Sach N, Shen H, Anders L, Boras B, Cao F, Cianfrogna JA, Cox L, Marroquin L, Pascual B, Petroski M, Quinlan C, Sacaan A, Wei N, Nair SK J Med Chem. 2025 Dec 5. doi: 10.1021/acs.jmedchem.5c02137. PMID:41347260[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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