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Bioorg Med Chem Lett. 2014 Jan 1;24(1):199-203. doi: 10.1016/j.bmcl.2013.11.041. Epub 2013 Nov 23.

Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor.

Author information

1
Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. Electronic address: yongqi.deng@merck.com.
2
Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
3
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
4
Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
5
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: william.windsor@merck.com.

Abstract

A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005μM.

KEYWORDS:

CDK2; High throughput screening; Kinases; Modulator; Tumor

PMID:
24332088
DOI:
10.1016/j.bmcl.2013.11.041
[Indexed for MEDLINE]

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