TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale d'un composé appelé TTT-3002, un inhibiteur de FLT3, pour le traitement d'une leucémie myéloïde aiguë présentant des mutations activatrices du gène FLT3
Greater 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 utilizing human FLT3/ITD mutant leukemia cell lines revealed the half maximal inhibitory concentration (IC50) for inhibiting FLT3 autophosphorylation is 100-250pM. The proliferation IC50 for TTT-3002 in these same cells was 490-920pM. TTT-3002 also showed potent activity when tested against the most frequently occurring FLT3 activating point mutation, FLT3/D835Y, against which many current TKI are ineffective. These findings were validated in vivo utilizing mouse models of FLT3-associated AML. Survival and tumor burden of mice in a number of FLT3/ITD transplant 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.
Blood 2014