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Tetrahydroindazole inhibitors of CDK2/cyclin complexes.

Authors:
Jae Chul Lee Kwon Ho Hong Andreas Becker Joseph S Tash Ernst Schönbrunn Gunda I Georg

Eur J Med Chem 2021 Mar 31;214:113232. Epub 2021 Jan 31.

Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN, 55455, USA. Electronic address:

Over 50 tetrahydroindazoles were synthesized after 7-bromo-3,6,6-trimethyl-1-(pyridin-2-yl)-5,6,7,7a-tetrahydro-1H-indazol-4(3aH)-one (3) was identified as a hit compound in a high throughput screen for inhibition of CDK2 in complex with cyclin A. The activity of the most promising analogues was evaluated by inhibition of CDK2 enzyme complexes with various cyclins. Analogues 53 and 59 showed 3-fold better binding affinity for CDK2 and 2- to 10-fold improved inhibitory activity against CDK2/cyclin A1, E, and O compared to screening hit 3. The data from the enzyme and binding assays indicate that the binding of the analogues to a CDK2/cyclin complex is favored over binding to free CDK2. Computational analysis was used to predict a potential binding site at the CDK2/cyclin E1 interface.

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http://dx.doi.org/10.1016/j.ejmech.2021.113232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954990PMC
March 2021

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