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

Faber, Erik B.; Sun, Luxin; Tang, Jian; Roberts, Emily; Ganeshkumar, Sornakala; Wang, Nan; Rasmussen, Damien; Majumdar, Abir; Hirsch, Laura E.; John, Kristen; Yang, An; Khalid, Hira; Hawkinson, Jon E.; Levinson, Nicholas M.; Chennathukuzhi, Vargheese; Harki, Daniel A.; Schönbrunn, Ernst; Georg, Gunda I.

doi:10.1038/s41467-023-38732-x

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

Journal Article · Sat Jun 03 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-38732-x· OSTI ID:2423378

^[1]; ^[2]; Tang, Jian ^[1]; ^[3]; ^[3]; ^[1]; ^[1]; ^[1]; ^[1]; John, Kristen ^[1]; Yang, An ^[1]; ^[1]; ^[1]; ^[1]; ^[3]; ^[1]; ^[2]; ^[1]

University of Minnesota, Minneapolis, MN (United States)
Moffitt Cancer Center, Tampa, FL (United States)
University of Kansas, Kansas City, KS (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Minnesota Ovarian Cancer Alliance (G.I.G.); NICHD; NIH/NCI; NIH/NIGMS; National Cancer Institute; The Moffitt Chemical Biology Core; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423378

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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

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