Aromatic interactions with phenylalanine 691 and cysteine 828: a concept for FMS-like tyrosine kinase-3 inhibition. Application to the discovery of a new class of potential antileukemia agents

  • J Med Chem. 2006 Jul 27;49(15):4451-4. doi: 10.1021/jm060368s.
Pascal Furet  1 ,  Guido Bold ,  Thomas Meyer ,  Johannes Roesel ,  Vito Guagnano
Affiliations
  • 1. Novartis Pharma AG, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland. [email protected]
PMID: 16854049 DOI: 10.1021/jm060368s
Abstract

FLT3 kinase inhibitors are currently under investigation as a new treatment for acute myeloid leukemia. We report here a molecular concept invoking interactions between an aromatic ring and the side chains of Phe691 and Cys828, two residues of the ATP pocket, to obtain potent and specific inhibitors of this kinase. The hypothesis has been validated by the successful design of a new inhibitor prototype showing promising antiproliferative activity in cellular assays.

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