title: TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo.
abstract: More than 35% of acute myeloid leukemia (AML) patients harbor a constitutively activating mutation in FMS-like tyrosine kinase-3 (FLT3). The most common type, internal tandem duplication (ITD), confers poor prognosis. We report for the first time on TTT-3002, a tyrosine kinase inhibitor (TKI) that is one of the most potent FLT3 inhibitors discovered to date. Studies using human FLT3/ITD mutant leukemia cell lines revealed the half maximal inhibitory concentration (IC50) for inhibiting FLT3 autophosphorylation is from 100 to 250 pM. The proliferation IC50 for TTT-3002 in these same cells was from 490 to 920 pM. TTT-3002 also showed potent activity when tested against the most frequently occurring FLT3-activating point mutation, FLT3/D835Y, against which many current TKIs are ineffective. These findings were validated in vivo by using mouse models of FLT3-associated AML. Survival and tumor burden of mice in several FLT3/ITD transplantation models is significantly improved by administration of TTT-3002 via oral dosing. Finally, we demonstrated that TTT-3002 is cytotoxic to leukemic blasts isolated from FLT3/ITD-expressing AML patients, while displaying minimal toxicity to normal hematopoietic stem/progenitor cells from healthy blood and bone marrow donors. Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI in the treatment of FLT3-mutant AML.
authors.affiliation: Departments of Oncology.
authors.forename: Hayley
authors.initials: H
authors.lastname: Ma
authors.forename: Bao
authors.initials: B
authors.lastname: Nguyen
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Greenblatt
authors.forename: Allen
authors.initials: A
authors.lastname: Williams
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Mark
authors.initials: M
authors.lastname: Levis
authors.forename: Michelle
authors.initials: M
authors.lastname: Rudek
authors.forename: Amy
authors.initials: A
authors.lastname: Duffield
authors.forename: Donald
authors.initials: D
authors.lastname: Small
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D020440:Gene Duplication; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020080:Tandem Repeat Sequences; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C588240:TTT-3002; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3