9PE7

CDK6 to CDK4 active site surrogate in complex with compound 6

This is a non-PDB format compatible entry.

Summary for 9PE7

• Entry DOI: 10.2210/pdb9pe7/pdb
• Descriptor: Cyclin-dependent kinase 6, (3R,4R)-4-({(4M)-5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-1,3-benzimidazol-6-yl]pyrimidin-2-yl}amino)-1-(methanesulfonyl)piperidin-3-ol (3 entities in total)
• Functional Keywords: kinase, cell cycle, cancer, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35498.76

Authors

Johnson, E.,Chen, P. (deposition date: 2025-07-01, release date: 2025-12-17)

Primary citation

Gallego, G.M.,Palmer, C.,Orr, S.,Bernier, L.,Chen, P.,Cho-Schultz, S.,Deal, J.G.,Dress, K.,Edwards, M.,Jalaie, M.,Johnson, E.,Kania, R.,Kath, J.C.,Lafontaine, J.,Ninkovic, S.,Sach, N.,Shen, H.,Anders, L.,Boras, B.,Cao, F.,Cianfrogna, J.A.,Cox, L.,Marroquin, L.,Pascual, B.,Petroski, M.,Quinlan, C.,Sacaan, A.,Wei, N.,Nair, S.K.
Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor.
J.Med.Chem., 2025

PubMed Abstract: Inhibitors 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.

PubMed: 41347260
DOI: 10.1021/acs.jmedchem.5c02137

Experimental method

X-RAY DIFFRACTION (2.05 Å)