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

Erik B. Faber, Luxin Sun, Jian Tang, Emily Roberts, Sornakala Ganeshkumar, Nan Wang, Damien Rasmussen, Abir Majumdar, Laura E. Hirsch, Kristen John, An Yang, Hira Khalid, Jon E. Hawkinson, Nicholas M. Levinson, Vargheese Chennathukuzhi, Daniel A. Harki, Ernst Schönbrunn and Gunda I. Georg ()
Additional contact information
Erik B. Faber: University of Minnesota College of Pharmacy—Twin Cities
Luxin Sun: Moffitt Cancer Center
Jian Tang: University of Minnesota College of Pharmacy—Twin Cities
Emily Roberts: University of Kansas Medical Center
Sornakala Ganeshkumar: University of Kansas Medical Center
Nan Wang: University of Minnesota College of Pharmacy—Twin Cities
Damien Rasmussen: University of Minnesota Medical School—Twin Cities
Abir Majumdar: University of Minnesota Medical School—Twin Cities
Laura E. Hirsch: University of Minnesota College of Pharmacy—Twin Cities
Kristen John: University of Minnesota College of Pharmacy—Twin Cities
An Yang: University of Minnesota College of Pharmacy—Twin Cities
Hira Khalid: University of Minnesota College of Pharmacy—Twin Cities
Jon E. Hawkinson: University of Minnesota College of Pharmacy—Twin Cities
Nicholas M. Levinson: University of Minnesota Medical School—Twin Cities
Vargheese Chennathukuzhi: University of Kansas Medical Center
Daniel A. Harki: University of Minnesota College of Pharmacy—Twin Cities
Ernst Schönbrunn: Moffitt Cancer Center
Gunda I. Georg: University of Minnesota College of Pharmacy—Twin Cities

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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 negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2-/- and Spdya-/- phenotypes.

Date: 2023
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DOI: 10.1038/s41467-023-38732-x

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