HDZ-740, a Potent FLT3 Inhibitor to Overcome FLT3 Mutations of Acute Myeloid Leukemia

Abstract

Abstract Acute myeloid leukemia (AML) is a life-threatening cancer characterized by a five-year survival rate of less than 30%. A pivotal target for AML therapy is an activating mutation in Fms-like tyrosine kinase 3 (FLT3), known as FLT3-ITD, which has been identified as a critical factor in disease progression. Despite the clinical development of three FLT3 inhibitors, resistance to these drugs often emerges, leading to relapse in patients. In this context, we have developed a novel marine-derived compound, namely HDZ-740, which has demonstrated a specific ability to inhibit the proliferation of AML cells carrying the FLT3-ITD mutation. Furthermore, HDZ-740 markedly impeded the growth of BaF3 cells expressing FLT3-ITD-TKD mutations, including D835V, D835Y, Y842C, Y842H, F691L, N676K, as well as AML blasts from patients with FLT3-ITD mutations. HDZ-740 has also shown inhibitory effects in environments conducive to drug resistance, such as under the protection of stromal cells. In vivo, HDZ-740 effectively hindered the expansion of AML cells with the FLT3-ITD mutation. Collectively, these findings underscore the potential of HDZ-740 as an effective therapeutic agent for treating AML patients harboring diverse FLT3-ITD and FLT3-TKD mutations and highlight its capability to circumvent mechanisms of drug resistance.