The FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase with important roles in hematopoietic stem/progenitor cell survival and proliferation. FLT3 is over-expressed in the majority of acute myeloid leukemia (AML) and the presence of FLT3 active mutations is associated with poor prognosis, implicating FLT3 as a potential target for AML treatment. ITRI-260 is a new azaazulenone class kinase inhibitor that inhibited FLT3-ITD-dependent MV4-11 cell growth with IC50 of 21 nM and cellular phosphorylation with IC50 of 17 nM. In in vivo PK study, ITRI-260 showed favorable oral PK profiles. The maximum concentration of ITRI-260 was 700 nM after a single 100 mg/kg oral dosing in mice, with dose proportional exposure from 10 to 150 mg/kg. ITRI-260 showed therapeutic efficacy in a human AML orthotopic SCID mouse model, following a 100 mg/kg/qd oral dosing regimen. The treatment group showed 100% survival of animals at day 90 after tumor cell inoculation, while the vehicle control group showed 100% mortality. In the other study, ITRI-260 also increased survival in primary tumor cell engraftment model inoculated with cells isolated from sunitinib- and sorafenib-resistant AML patient. Through hERG assay with patch clamp technology, we found higher IC50 of ITIR-260 compared with sunitinib and MLN-518, which indicates that ITRI-260 might arise less cardiotoxic concern. In a 14-day subchronic toxicology study in mice, ITRI-260 was generally tolerated at 300 mg/kg/qd. The most prominent adverse effect appeared at 600 mg/kg/qd group is starry sky appearance in spleen, which is moderate and reversible. No specific clinical signs or body weight loss were attributed to the test article. In conclusion, the in vitro/in vivo PK/PD/toxicology studies have provided the basis for the clinical developmental potential of ITRI-260 in AML. The bridge studies from discovery to development such as CMC, GLP toxicology/safety pharmacology and pre-formulation are now in progress.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5781.