1. Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors.
- Author
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Grimm SH, Gagestein B, Keijzer JF, Liu N, Wijdeven RH, Lenselink EB, Tuin AW, van den Nieuwendijk AMCH, van Westen GJP, van Boeckel CAA, Overkleeft HS, Neefjes J, and van der Stelt M
- Subjects
- Aza Compounds chemical synthesis, Aza Compounds metabolism, Binding Sites, Humans, Indoles chemical synthesis, Indoles metabolism, Molecular Docking Simulation, Molecular Structure, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Structure-Activity Relationship, fms-Like Tyrosine Kinase 3 chemistry, fms-Like Tyrosine Kinase 3 metabolism, Aza Compounds chemistry, Indoles chemistry, Protein Kinase Inhibitors chemistry, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
Acute myeloid leukemia (AML) is characterized by fast progression and low survival rates, in which Fms-like tyrosine kinase 3 (FLT3) receptor mutations have been identified as a driver mutation in cancer progression in a subgroup of AML patients. Clinical trials have shown emergence of drug resistant mutants, emphasizing the ongoing need for new chemical matter to enable the treatment of this disease. Here, we present the discovery and topological structure-activity relationship (SAR) study of analogs of isoquinolinesulfonamide H-89, a well-known PKA inhibitor, as FLT3 inhibitors. Surprisingly, we found that the SAR was not consistent with the observed binding mode of H-89 in PKA. Matched molecular pair analysis resulted in the identification of highly active sub-nanomolar azaindoles as novel FLT3-inhibitors. Structure based modelling using the FLT3 crystal structure suggested an alternative, flipped binding orientation of the new inhibitors., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2019
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