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Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

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,van der Stelt M

doi

10.1016/j.bmc.2019.01.006

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

692-699

issue

5

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(18)31968-0

journal_volume

27

pub_type

杂志文章

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