6OQO

CDK6 in complex with Cpd24 N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyrimidin-2-amine

Summary for 6OQO

• Entry DOI: 10.2210/pdb6oqo/pdb
• Related: 6OQL
• Descriptor: Cyclin-dependent kinase 6, N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine (3 entities in total)
• Functional Keywords: kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33531.62

Authors

Murray, J.M.,Boenig, G.D.L. (deposition date: 2019-04-26, release date: 2020-07-29, Last modification date: 2024-05-22)

Primary citation

Bronner, S.M.,Merrick, K.A.,Murray, J.,Salphati, L.,Moffat, J.G.,Pang, J.,Sneeringer, C.J.,Dompe, N.,Cyr, P.,Purkey, H.,Boenig, G.L.,Li, J.,Kolesnikov, A.,Larouche-Gauthier, R.,Lai, K.W.,Shen, X.,Aubert-Nicol, S.,Chen, Y.C.,Cheong, J.,Crawford, J.J.,Hafner, M.,Haghshenas, P.,Jakalian, A.,Leclerc, J.P.,Lim, N.K.,O'Brien, T.,Plise, E.G.,Shalan, H.,Sturino, C.,Wai, J.,Xiao, Y.,Yin, J.,Zhao, L.,Gould, S.,Olivero, A.,Heffron, T.P.
Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma.
Bioorg.Med.Chem.Lett., 29:2294-2301, 2019

PubMed Abstract: CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MW = 285 and TPSA = 66 Å), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpK = 8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse K = 0.20-0.59). To probe the potency and selectivity, our lead compound was evaluated in a panel of glioblastoma cell lines. Potency comparable to abemaciclib was observed in Rb-wild type lines U87MG, DBTRG-05MG, A172, and T98G, while Rb-deficient cell lines SF539 and M059J exhibited a lack of sensitivity.

PubMed: 31307887
DOI: 10.1016/j.bmcl.2019.06.021

Experimental method

X-RAY DIFFRACTION (1.977 Å)