2. Academic Validation
  3. Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2

Structure-based design of potent and selective 2-(quinazolin-2-yl)phenol inhibitors of checkpoint kinase 2

  • J Med Chem. 2011 Jan 27;54(2):580-90. doi: 10.1021/jm101150b.
John J Caldwell 1,  Emma J Welsh,  Cornelis Matijssen,  Victoria E Anderson,  Laurent Antoni,  Kathy Boxall,  Frederique Urban,  Angela Hayes,  Florence I Raynaud,  Laurent J M Rigoreau,  Tony Raynham,  G Wynne Aherne,  Laurence H Pearl,  Antony W Oliver,  Michelle D Garrett,  Ian Collins
Affiliations

Affiliation

  • 1 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. john.caldwell@icr.ac.uk
PMID: 21186793 DOI: 10.1021/jm101150b
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 (IC(50) 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).

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