Profiling of the kinase-binding capabilities of an aminopyrimidine analogue detected in a cellular screen of the St. Jude small-molecule collection led to the identification of a novel series of FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure–activity relationship studies led to the development of compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless of their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound 5e shows characteristics suitable for further preclinical development.

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Published in ACS Omega, v. 2, issue 5, p. 1985-2009.

Copyright © 2017 American Chemical Society

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

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This work was supported by the Department of Defense (CA093469P2), NCI (CA138744-07), St. Jude Children’s Research Hospital, and the American Lebanese Syrian Associated Charities (ALSAC).

Related Content

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00144.

ao7b00144_si_001.pdf (280 kB)
Experimental procedures for ADME and MTD studies; additional experimental procedures for synthesis and characterization of compounds; additional synthetic schemes for preparation of intermediates; KinomeScan analysis for compound 1; growth inhibition data against the BJ cell line for all compounds; FLT3 inhibition and MV4-11 cell proliferation data, including CI 95; solubility and permeability data for selected compounds; cellular permeability and PGP efflux assay data; in vivo blood chemistry data after i.p. dosing of compound 5e in mice (PDF)

ao7b00144_si_002.xlsx (17 kB)
Experimental data for compounds 1, 4–6, 9, 13, 14, 16, 17, and 19–22 (XLSX)