Design and synthesis of thiadiazoles and thiazoles targeting the Bcr-Abl T315I mutant: From docking false positives to ATP-noncompetitive inhibitors

Abstract

(Figure Presented) Overcoming resistance: In an effort to optimize our previously identified dual Src/Abl hits, a new series of 1,3,4-thiadiazoles and 1,3-thiazoles were designed and synthesized, paying particular attention to the reduction of their lipophilicity and to the improvement of the affinity towards the drug-resistant T315I mutant. Compound 5 was identified as a promising allosteric inhibitor of the T315I mutant. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.