Inhibition of enzymes that participate in the cell cycle is a valuable approach to targeted cancer therapy. The cyclin-dependent kinase (CDK) family of enzymes plays a key role in the regulation of the mitotic cell cycle, and dysfunctional CDK activity has been observed in essentially all cancers. CDK2, which facilitates transition through two phases of the cell cycle, is overexpressed in a range of tumors including breast and colorectal cancer, and melanoma. Modulation of CDK2 activity with small-molecule inhibitors has been demonstrated to elicit selective antitumor activity.We have previously identified potent and selective CDK2 inhibitors, exemplified by the 6-alkoxypurine derivative NU6102. The vinylsulfone analogue NU6300 (1 ) was subsequently found to inhibit CDK2 in a time-dependent manner. The compound reacts covalently with CDK2, specifically by Michael addition of a lysine residue (Lys89), located in the 'hinge region' of the ATP-binding domain, to the vinylsulfone of 1 . However, the high reactivity of NU6300 was found to compromise selectivity and chemical stability, and further optimisation was required.Using the crystal structure of the CDK2-NU6300 complex as a guide to inhibitor design, analogues (2 ) were synthesized bearing substituents (R) on the vinylsulfone group, predicted to attenuate reactivity whilst retaining the required potency against CDK2. The design, synthesis and biological activity of this new series of irreversible CDK2 inhibitors and their corresponding hydrolysis products (3 ), which are putative ATP-competitive inhibitors, will be discussed.

Anticancer agents targeted against cyclin-dependent kinase 2 (CDK2): Structure-based design of irreversible and reversible inhibitors

247th National Meeting (2014)

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