Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target

Abstract

Deregulation of cyclin-dependent kinases (CDKs) has been associated with many cancer types and has evoked an interest in chemical inhibitors with possible therapeutic benefit. While most known inhibitors display broad selectivity towards multiple CDKs, recent work highlights CDK9 as the critical target responsible for the anticancer activity of clinically evaluated drugs. In this review, we discuss recent findings provided by structural biologists that may allow further development of highly specific inhibitors of CDK9 towards applications in cancer therapy. We also highlight the role of CDK9 in inflammatory processes and diseases.

Fig. (1)

CDK inhibitors for which cocrystal structures with CDK9/cyclinT are available.

Fig. (2)

Structure and inhibitor binding of CDK9. A: Ribbon model of CDK9/cyclin T (pdb id: 3BLQ) in green and grey, respectively. ATP is represented as a yellow stick model and the different elements of the kinase fold are indicated. B: Superposition of CDK9/cyclin T ATP (grey, pdb id: 3BLQ [33]) and DRB (lime green, pdb id: 3MY1 [37]) bound structures. Both structures where superposed on their C-terminal kinase domains. CDK9 is represented as ribbon, ATP and DRB as stick models, respectively. C: Structures of CDK9 bound SCR8 (pdb id: 3LQ5 [36]) and flavopiridol (pdb id: 3BLR). Same view as in B.

Fig. (3)

Structures of some clinically evaluated CDK inhibitors discussed in the review.