1. Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors
- Author
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Sebastian H. Grimm, Eelke B. Lenselink, Adriaan W. Tuin, Constant A. A. van Boeckel, Adrianus M. C. H. van den Nieuwendijk, Ruud H. Wijdeven, Jordi F. Keijzer, Mario van der Stelt, Herman S. Overkleeft, Jacques Neefjes, Nora Liu, Gerard J. P. van Westen, and Berend Gagestein
- Subjects
Fms-like tyrosine kinase 3 (FLT3) ,Indoles ,Acutemyeloidleukemia(AML) ,Clinical Biochemistry ,Pharmaceutical Science ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,hemic and lymphatic diseases ,Drug Discovery ,Acute myeloid leukemia (AML) ,medicine ,Humans ,Structure–activity relationship ,Receptor ,Protein Kinase Inhibitors ,Fms-liketyrosinekinase3(FLT3) ,Molecular Biology ,Aza Compounds ,Mutation ,Binding Sites ,Molecular Structure ,Inhibitors ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Cancer ,Myeloid leukemia ,Drug resistant mutants ,medicine.disease ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,fms-Like Tyrosine Kinase 3 ,H-89analogs ,Tyrosine Kinase 3 ,Cancer research ,H-89 analogs ,Molecular Medicine ,Matched molecular pair analysis ,Protein Binding - 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.
- Published
- 2019