title: Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia.
abstract: A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N(3)-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.
authors.affiliation: Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139, United States. robert_davies@vrtx.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Davies
authors.forename: Albert C
authors.initials: AC
authors.lastname: Pierce
authors.forename: Cornelia
authors.initials: C
authors.lastname: Forster
authors.forename: Ron
authors.initials: R
authors.lastname: Grey
authors.forename: Jinwang
authors.initials: J
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Arnost
authors.forename: Deborah
authors.initials: D
authors.lastname: Choquette
authors.forename: Vincent
authors.initials: V
authors.lastname: Galullo
authors.forename: Shi-Kai
authors.initials: SK
authors.lastname: Tian
authors.forename: Greg
authors.initials: G
authors.lastname: Henkel
authors.forename: Guanjing
authors.initials: G
authors.lastname: Chen
authors.forename: David K
authors.initials: DK
authors.lastname: Heidary
authors.forename: Joanne
authors.initials: J
authors.lastname: Ma
authors.forename: Cameron
authors.initials: C
authors.lastname: Stuver-Moody
authors.forename: Mark
authors.initials: M
authors.lastname: Namchuk
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D009025:Morpholines; C568953:N3-(4-(4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine; D014230:Triazoles; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3