Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

DOI: 10.1021/jm101150b
PMID: 21186793

Authors: John J. Caldwell (The Institute of Cancer Research) , Emma J. Welsh (The Institute of Cancer Research) , Cornelis Matijssen (The Institute of Cancer Research) , Victoria E. Anderson (The Institute of Cancer Research) , Laurent Antoni (The Institute of Cancer Research) , Kathy Boxall (The Institute of Cancer Research) , Frederique Urban (The Institute of Cancer Research) , Angela Hayes (The Institute of Cancer Research) , Florence I. Raynaud (The Institute of Cancer Research) , Laurent J. M. Rigoreau (Wolfson Institute for Biomedical Research) , Tony Raynham (Wolfson Institute for Biomedical Research) , G. Wynne Aherne (The Institute of Cancer Research) , Laurence H. Pearl (The Institute of Cancer Research) , Antony W. Oliver (The Institute of Cancer Research) , Michelle D. Garrett (The Institute of Cancer Research) , Ian Collins (The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 54 (2) , PAGES 580 - 590

State: Published (Approved)
Published: January 2011
Diamond Proposal Number(s): 6385

Abstract: Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure?activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC50 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

Journal Keywords: Apoptosis; Cell; Checkpoint; Crystallography; X-Ray; Drug; Ether-A-Go-Go; HT29; Humans; In; Mice; Models; Molecular; Phenols; Protein; Protein-Serine-Threonine; Quinazolines; Radiation-Protective; Stereoisomerism; Structure-Activity; Thymus Gland

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: ID14-2 at ESRF; X10SA at SLS

Added On: 29/09/2011 18:03

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)