4EZ5

CDK6 (monomeric) in complex with inhibitor

Summary for 4EZ5

• Entry DOI: 10.2210/pdb4ez5/pdb
• Related: 3NUP 3NUX
• Descriptor: Cyclin-dependent kinase 6, {5-[4-(dimethylamino)piperidin-1-yl]-1H-imidazo[4,5-b]pyridin-2-yl}[2-(isoquinolin-4-yl)pyridin-4-yl]methanone (2 entities in total)
• Functional Keywords: protein kinase, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q00534
• Total number of polymer chains: 1
• Total formula weight: 35496.77

Authors

Chopra, R.,Xu, M. (deposition date: 2012-05-02, release date: 2013-02-06, Last modification date: 2023-09-13)

Primary citation

Cho, Y.S.,Angove, H.,Brain, C.,Chen, C.H.,Cheng, H.,Cheng, R.,Chopra, R.,Chung, K.,Congreve, M.,Dagostin, C.,Davis, D.J.,Feltell, R.,Giraldes, J.,Hiscock, S.D.,Kim, S.,Kovats, S.,Lagu, B.,Lewry, K.,Loo, A.,Lu, Y.,Luzzio, M.,Maniara, W.,McMenamin, R.,Mortenson, P.N.,Benning, R.,O'Reilly, M.,Rees, D.C.,Shen, J.,Smith, T.,Wang, Y.,Williams, G.,Woolford, A.J.,Wrona, W.,Xu, M.,Yang, F.,Howard, S.
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
ACS Med Chem Lett, 3:445-449, 2012

PubMed Abstract: Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.

PubMed: 24900493
DOI: 10.1021/ml200241a

Experimental method

X-RAY DIFFRACTION (2.7 Å)