Tetrahydroindazole inhibitors of CDK2/cyclin complexes

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

doi:10.1016/j.ejmech.2021.113232

Tetrahydroindazole inhibitors of CDK2/cyclin complexes

Eur J Med Chem. 2021 Mar 15:214:113232. doi: 10.1016/j.ejmech.2021.113232. Epub 2021 Jan 31.

Authors

Jae Chul Lee¹, Kwon Ho Hong¹, Andreas Becker¹, Joseph S Tash², Ernst Schönbrunn³, Gunda I Georg⁴

Affiliations

¹ Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN, 55455, USA.
² Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
³ Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
⁴ 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: georg@umn.edu.

Abstract

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.

Keywords: CDK2; Cyclins; Kinase inhibitors; Tetrahydroindazoles.

MeSH terms

Binding Sites / drug effects
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
Cyclin-Dependent Kinase 2 / metabolism
Cyclins / antagonists & inhibitors*
Cyclins / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
MCF-7 Cells
Molecular Structure
Structure-Activity Relationship

Substances

Cyclins
Enzyme Inhibitors
Indazoles
CDK2 protein, human
Cyclin-Dependent Kinase 2

Grants and funding

HHSN275200503400C/HD/NICHD NIH HHS/United States