9d8u
Crystal structure of CDK6 in complex with atirmociclib
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 PubMedCDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2-) breast cancer. Yet, all "dual" CDK4/6 inhibitors show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at concentrations necessary to extinguish cell cycling in tumors. HR+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, due to the primary and compensatory role of CDK6 in hematopoiesis. This prompted us to develop atirmociclib (PF-07220060), a next-generation CDK4 selective inhibitor. Atirmociclib's impact on circulating neutrophils was reduced, in proportion with its increase in CDK4 versus CDK6 selectivity. Realized dose intensification led to greater CDK4 inhibition and deeper anti-tumor responses, pointing to CDK4 target coverage as a limiting factor of CDK4/6 inhibitor efficacy. We also highlight combinatorial agents that may counter acquired resistance to CDK4 selective inhibition and widen its clinical application. CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety.,Palmer CL, Boras B, Pascual B, Li N, Li D, Garza S, Huser N, Yuan JT, Cianfrogna JA, Sung T, McMillan E, Wei N, Carmody J, Kang AN, Darensburg S, Dodd T, Oakley JV, Solowiej J, Nguyen L, Orr STM, Chen P, Johnson E, Yu X, Diehl WC, Gallego GM, Jalaie M, Ferre RA, Cho-Schultz S, Shen H, Deal JG, Zhang Q, Baffi TR, Xu M, Roh W, Lapira-Miller J, Goudeau J, Yu Y, Gupta R, Kim K, Dann SG, Kan Z, Kath JC, Nair SK, Miller N, Murray BW, Nager AR, Quinlan C, Petroski MD, Zhang C, Sacaan A, VanArsdale T, Anders L Cancer Cell. 2025 Mar 10;43(3):464-481.e14. doi: 10.1016/j.ccell.2025.02.006. PMID:40068598[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
