Georg and Harki Labs Collaborate on CDK2 Discovery
June 20, 2023
The laboratories of Dr. Gunda Georg and Dr. Daniel Harki collaborated on a recent publication in Nature Communications regarding the discovery of a new allosteric inhibitors that bind to CDK2.
Cyclin-dependent kinase 2 (CDK2), part of the enzyme family responsible for controlling the cell cycle, is a target for both several types of cancer and male contraception.
The paper describes the development and mechanism of action of new allosteric inhibitors that tightly bind CDK2 in a part of protein away from the traditionally targeted active site, making them the highest affinity, structurally confirmed allosteric CDK inhibitors reported.
By targeting an allosteric pocket, these inhibitors hold promise to be more selective than previous CDK2 inhibitors that targeted the active site, as the active site structure is similar among many kinases. In both biophysical and cellular assays, this series showed selectivity for CDK2 over highly similar kinases like CDK1, suggesting their promise for further development into a selective but efficacious therapeutic.
Additionally, the potential of these inhibitors as efficacious contraceptive agents was observed in mouse testicular explant models.
Link to publication:
Faber, E. B., Sun, L., Tang, J., Roberts, E., Ganeshkumar, S., Wang, N., Rasmussen, D., Majumdar, A., Hirsch, L. E., John, K., Yang, A., Khalid, H., Hawkinson, J. E., Levinson, N. M., Chennathukuzhi, V., Harki, D. A., Schönbrunn, E., and Georg, G. I. (2023) Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding, Nat Commun 14, 3213.