4BCN

Structure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor

Summary for 4BCN

• Entry DOI: 10.2210/pdb4bcn/pdb
• Related: 4BCF 4BCG 4BCH 4BCI 4BCJ 4BCK 4BCM 4BCO 4BCP 4BCQ
• Descriptor: CYCLIN-DEPENDENT KINASE 2, CYCLIN-A2, 2-[(3-hydroxyphenyl)amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile, ... (6 entities in total)
• Functional Keywords: transferase-cell cycle complex, cdk-cyclin complex, cyclin-inhibitor, structure-based drug design, transferase/cell cycle
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, cytoskeleton, centrosome: P24941; Nucleus: P20248 P20248
• Total number of polymer chains: 4
• Total formula weight: 129384.56

Authors

Hole, A.J.,Baumli, S.,Wang, S.,Endicott, J.A.,Noble, M.E.M. (deposition date: 2012-10-02, release date: 2013-03-06)

Primary citation

Hole, A.J.,Baumli, S.,Shao, H.,Shi, S.,Pepper, C.,Fischer, P.M.,Wang, S.,Endicott, J.A.,Noble, M.E.M.
Comparative Structural and Functional Studies of 4-(Thiazol- 5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9 Inhibitors Suggest the Basis for Isotype Selectivity.
J.Med.Chem., 56:660-, 2013

PubMed Abstract: Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.

PubMed: 23252711
DOI: 10.1021/JM301495V

Experimental method

X-RAY DIFFRACTION (2.1 Å)