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

Sebastian H Grimm; Berend Gagestein; Jordi F Keijzer; Nora Liu; Ruud H Wijdeven; Eelke B Lenselink; Adriaan W Tuin; Adrianus M C H van den Nieuwendijk; Gerard J P van Westen; Constant A A van Boeckel; Herman S Overkleeft; Jacques Neefjes; Mario van der Stelt

doi:10.1016/j.bmc.2019.01.006

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

Bioorg Med Chem. 2019 Mar 1;27(5):692-699. doi: 10.1016/j.bmc.2019.01.006. Epub 2019 Jan 14.

Affiliations

¹ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
² Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
³ Computational Drug Discovery, Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
⁴ Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
⁵ Pivot Park Screening Center, Oss, the Netherlands.
⁶ Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands. Electronic address: m.van.der.stelt@chem.leidenuniv.nl.

PMID: 30661740
DOI: 10.1016/j.bmc.2019.01.006

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.

Keywords: Acute myeloid leukemia (AML); Fms-like tyrosine kinase 3 (FLT3); H-89 analogs; Inhibitors.

MeSH terms

Aza Compounds / chemical synthesis
Aza Compounds / chemistry*
Aza Compounds / metabolism
Binding Sites
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / metabolism
Molecular Docking Simulation
Molecular Structure
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / chemistry
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Aza Compounds
Indoles
Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3