title: Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.
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.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hole
authors.forename: Sonja
authors.initials: S
authors.lastname: Baumli
authors.forename: Hao
authors.initials: H
authors.lastname: Shao
authors.forename: Shenhua
authors.initials: S
authors.lastname: Shi
authors.forename: Shiliang
authors.initials: S
authors.lastname: Huang
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Peter M
authors.initials: PM
authors.lastname: Fischer
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Martin E
authors.initials: ME
authors.lastname: Noble
mesh_terms: D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9