Blood Journal
Leading the way in experimental and clinical research in hematology

TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo

  1. Hayley Ma1,
  2. Bao Nguyen1,
  3. Li Li1,
  4. Sarah Greenblatt1,
  5. Allen Williams1,
  6. Ming Zhao1,
  7. Mark Levis1,
  8. Michelle Rudek1,
  9. Amy Duffield2, and
  10. Donald Small1,3
  1. 1Departments of Oncology,
  2. 2Pathology and
  3. 3Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD

Key Points

  • A novel TKI is discovered with potent and selective activity against FLT3-mutant cell lines and primary patient samples.

  • TTT-3002 is effective in vivo in several mouse tumor models of FLT3/ITD-associated AML with minimal toxicity.


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.

  • Submitted August 24, 2013.
  • Accepted January 3, 2014.
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