Discovery of cmpd D6 (FH-001) as a efficiency enhancement and myelosuppression degradation small-molecule fms-like tyrosine kinase 3 inhibitor for the treatment of FLT3-ITD positive acute myeloid leukemia

Abstract

AML is the most common and lethal type of leukemia. The mutant of FLT3 kinase is the most common mutation in AML. Based on the structure analysis and deuteration modification of the cmpd 18 (CHMFL-FLT3-122), a potent and orally available FLT3 Kinase inhibitor, cmpd D6 (FH-001) was found, which demonstrated a remarkable inhibitory effect on the proliferation of FLT3 - ITD positive AML cancer cell lines. Specifically, it effectively suppressed the growth of the MV4-11 cell line (IC₅₀ = 42.8 nM versus 17.1 nM). Similarly, notable inhibitory activity was observed in the MOLM-13 (IC₅₀ = 20.8 nM versus 53.9 nM). More importantly, the IC₅₀ of cmpd D6 to inhibit FLT3 kinase was 338.689 nM and the IC₅₀ to inhibit c-KIT kinase was 3006.042 nM, which were much lower than the IC₅₀ of cmpd 18 to the two kinases, indicating that cmpd D6 may effectively avoid the synthetic lethal myelosuppression toxicity caused by FLT3/c-KIT double inhibition. Pharmacokinetic experiments showed that the deuterated cmpd D6 could prolong the half-life (T_1/2 = 4.333 h versus 3.646 h) and improve bioavailability (F = 42.51 % versus 35.93 %). Pharmacodynamic experiments of the three models showed that cmpd D6 (12.5 mg/kg) could significantly inhibit tumor growth compared with cmpd 18, and had no obvious toxicity. Based on the above results, cmpd D6 is a potential candidate drug for the future treatment of FLT3-ITD positive AML.