TY - JOUR
T1 - TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo
AU - Ma, Hayley
AU - Nguyen, Bao
AU - Li, Li
AU - Greenblatt, Sarah
AU - Williams, Allen
AU - Zhao, Ming
AU - Levis, Mark
AU - Rudek, Michelle
AU - Duffield, Amy
AU - Small, Donald
PY - 2014/3/6
Y1 - 2014/3/6
N2 - 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 themost 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 ML. Survival and tumor burden ofmice in several FLT3/ITD transplantationmodels 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.
AB - 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 themost 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 ML. Survival and tumor burden ofmice in several FLT3/ITD transplantationmodels 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.
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U2 - 10.1182/blood-2013-08-523035
DO - 10.1182/blood-2013-08-523035
M3 - Article
C2 - 24408321
AN - SCOPUS:84897557274
SN - 0006-4971
VL - 123
SP - 1525
EP - 1534
JO - Blood
JF - Blood
IS - 10
ER -