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

Deng, Y, Shipps, J, Zhao, L, Siddiqui, MA, Popovici-Muller, J, Curran, PJ, Duca, JS, Hruza, AW, Fischmann, TO, Madison, VS, Zhang, R, McNemar, CW, Mayhood, TW, Syto, R, Annis, A, Kirschmeier, P, Lees, EM, Parry, DA and Windsor, WT (2014) Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor. Bioorganic and Medicinal Chemistry Letters. pp. 199-203.


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 (K<sub>d</sub>) of the original hit improved from 1 to 0.005 muM. 2013 Elsevier Ltd. All rights reserved

Item Type: Article
Additional Information: NIBR author: Duca, JS institute: NIBR- address only contributor address: (Deng, Shipps Jr., Zhao, Siddiqui, Popovici-Muller, Curran, Duca, Annis) Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States (Hruza, Fischmann, Madison, Zhang, McNemar, Mayhood, Syto, Kirschmeier, Windsor) Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States (Lees, Parry) Merck Research Laboratories, 901 California Avenue, Palo Alto, CA 94304, United States (Shipps Jr.) New Venture Fund, Stoneham, MA 02180, United States (Siddiqui) Paraza Pharma, Inc., 500 Boulevard Cartier (West), Laval, QC H7V 5B7, Canada (Popovici-Muller) 38 Sidney Street, Cambridge, MA 02139-4169, United States (Duca) Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, MA 02139, United States (Annis) Aileron Therapeutics, Inc., 281 Albany St., Cambridge, MA 02139, United States (Kirschmeier) 106 Culberson Rd, Basking Ridge, NJ 07920, United States (Lees) Novartis Institutes for BioMedical Research, Emeryville, CA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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