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

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

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	113232
Journal	European Journal of Medicinal Chemistry
Volume	214
DOIs	https://doi.org/10.1016/j.ejmech.2021.113232
State	Published - Mar 15 2021

Bibliographical note

Funding Information:
We gratefully acknowledge financial support from the Contraception Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) through contract HHSN275200503400C. We thank Drs. H. K. Kim, Diana Blithe, and Min Lee from NICHD for their support of this project. Funding came from the NIH (US).

Funding Information:
We gratefully acknowledge financial support from the Contraception Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) through contract HHSN275200503400C . We thank Drs. H. K. Kim, Diana Blithe, and Min Lee from NICHD for their support of this project. Funding came from the NIH (US).

Publisher Copyright:
© 2021 Elsevier Masson SAS

Keywords

CDK2
Cyclins
Kinase inhibitors
Tetrahydroindazoles

PubMed: MeSH publication types

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10.1016/j.ejmech.2021.113232

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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.",

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AB - 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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Tetrahydroindazole inhibitors of CDK2/cyclin complexes

Abstract

Bibliographical note

Keywords

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