title: Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors.
abstract: The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Frett
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: McConnell
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, CA, USA.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Yuanxiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.affiliation: College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA; The University of Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ 85724, USA. Electronic address: hongyuli@pharmacy.arizona.edu.
authors.forename: Hong-yu
authors.initials: HY
authors.lastname: Li
mesh_terms: D000818:Animals; D002460:Cell Line / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D017076:Computer-Aided Design; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D046609:Libraries, Digital; D008024:Ligands; D051379:Mice; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D054852:Small Molecule Libraries; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: AML; Computer aided drug discovery; FLT3; Kinase inhibitor; Ligand efficiency