title: Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor.
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.
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA. Electronic address: yongqi.deng@merck.com.
authors: Yongqi
authors: Y
authors: Deng
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: Gerald W
authors: GW
authors: Shipps
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: Lianyun
authors: L
authors: Zhao
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: M Arshad
authors: MA
authors: Siddiqui
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: Janeta
authors: J
authors: Popovici-Muller
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: Patrick J
authors: PJ
authors: Curran
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: Jose S
authors: JS
authors: Duca
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Alan W
authors: AW
authors: Hruza
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Thierry O
authors: TO
authors: Fischmann
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Vincent S
authors: VS
authors: Madison
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Rumin
authors: R
authors: Zhang
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Charles W
authors: CW
authors: McNemar
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Todd W
authors: TW
authors: Mayhood
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Rosalinda
authors: R
authors: Syto
authors: Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, USA.
authors: Allen
authors: A
authors: Annis
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Paul
authors: P
authors: Kirschmeier
authors: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors: Emma M
authors: EM
authors: Lees
authors: Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, USA.
authors: David A
authors: DA
authors: Parry
authors: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: william.windsor@merck.com.
authors: William T
authors: WT
authors: Windsor
mesh_terms: D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019925:Cyclin A; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C037219:quinoline; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: CDK2; High throughput screening; Kinases; Modulator; Tumor