Abstract 2093: HEC73543 is a novel potent, selective Flt3 receptor tyrosine kinase (RTK) Inhibitor for the treatment of refractory acute myeloid leukemia (AML)
Authors: Cheng Cliff 
Published: July 2017

Background: Adults acute myeloid leukemia (AML) account for ~30% of leukemia and ~40% of leukemia-related deaths. FLT3 is a receptor tyrosine kinase that is normally expressed on immature hematopoietic cells and functions in the development of both stem cells and the immune system. FLT3 is the most frequently mutated gene in AML, with an estimated 30 % of AML patients harboring FLT3 mutations. FLT3-ITD is a common mutation in AML and correlates with a poor prognosis and higher risk of relapse of AML patients.

Methods and Results: HEC73543 is a potent, orally bioavailable small molecule tyrosine kinase inhibitor (TKI) against FLT3 which have been implicated in acute myeloid leukemia (AML) pathogenesis. In cell-based assays, HEC73543 showed IC50s = 1.5 and 1.4 nM against MV-4-11 and MOLM-13 cells in proliferation (both cell lines are FLT3-ITD+). Induction of apoptosis following treatment of FLT3-ITD leukemic MV-4-11 cells for 48 h was assayed by flow cytometry. In MV-4-11 cells, a concentration of 10 nM HEC73543 induced 64.8% of the cells to undergo apoptosis and had a dose dependent increase. When single dosed orally (4.5mg/kg) to MV-4-11 tumor-bearing nude mice, HEC73543 potently inhibited the phosphorylation of FLT3 and its downstream signaling kinases STAT5, AKT and ERK1/2 for up to 8 hours in tumor tissues. The antitumor activity of HEC73543 was evaluated using an FLT3-ITD subcutaneous tumor xenograft model (MV-4-11 and MOLM-13) in athymic mice. Groups of 8 tumor-bearing mice were treated with vehicle alone or with HEC73543 administered orally at 0.5, 1.5, or 4.5mg/kg/day. The compound was well tolerated and no significant body weight loss or lethality was observed. The antitumor activity of HEC73543 was dose dependent. At the 1.5 mg/kg/day dose level all animals had a complete regression (CR) in MV-4-11 model, and the CR induced by 4.5mg/kg/day in MOLM-13 model. HEC73543 can significant prolong mice survival time at 1 mg/kg/day dose level in MOLM-13 systemic xenograft model. We have studied cytotoxic interactions of HEC73543 with conventional antileukemic agents cytarabine using two leukemia cell lines carrying FLT3-ITD (MOLM-13, MV-4-11) The combination of HEC73543 with cytarabine produced additive effects in MV-4-11 and MOLM-13 cell lines. HEC73543 displayed excellent oral bioavailability and desirable drug exposures in mice, rats, dogs and monkeys.

Conclusions: Together, HEC73543 exhibits potent target inhibition and efficacy in FLT3-ITD models suggests that this compound may have a therapeutic benefit for patients with FLT3-ITD leukemia.

Citation Format: Cliff Cheng. HEC73543 is a novel potent, selective Flt3 receptor tyrosine kinase (RTK) Inhibitor for the treatment of refractory acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2093. doi:10.1158/1538-7445.AM2017-2093