Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding.

ABSTRACT: Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negativ

SUBMITTER: Faber EB 

PROVIDER: S-EPMC10239507 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature