Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 15, Pages 4324-4327Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.05.095
Keywords
BCR-ABL; Chronic myelogenous leukemia; T315I mutant; Structure-based design; Flavone
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Funding
- Wonkwang University
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The existence of drug resistance caused by mutations in the break-point cluster region-Abelson (BCR-ABL) tyrosine kinase domain remains a clinical challenge due to limited treatment options for effective CML therapies. Here, we report a series of flavone-based common inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of BCR-ABL. The original hit 1 was extensively modified through a structure-based drug design strategy, especially by varying the C7 acetamide appendage of the scaffold to exploit extended interactions with P-loop residues. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of ABL are discussed in detail. (C) 2013 Elsevier Ltd. All rights reserved.
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