Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone. Large chromosomal translocations, as well as mutations in the genes involved in hematopoietic proliferation and differentiation, result in the accumulation of poorly differentiated myeloid cells. AML with FMS-like tyrosine kinase 3 (FLT3) mutation has a high risk of relapse after therapy and reduced overall survival. Moreover, activating mutations of internal tandem duplication (ITD) and tyrosine kinase domain point mutations (TKD) of FLT3 have approximately 30% of AML as oncogenic driver mutations. The mutations of FLT3-TKD include D835Y and F691L. In this study, HM43239 is a novel FLT3 inhibitor. It has antitumor activity in acute myeloid leukemia. Moreover, HM43239 inhibits the proliferation and induces the apoptosis of leukemic cells.

HM43239 is a potent FLT3 inhibitor and shows effectiveness in AML with FLT3 mutations.

HM43239 is an orally active and selective FLT3 inhibitor with IC₅₀ of 1.1 nM for the FLT3 wild type. In addition, it shows IC₅₀s of 1.8 nM (FLT3 ITD mutants) and 1.0 nM (FLT3 D835Y mutants), respectively. Moreover, it inhibits the kinase activity of FLT3 as a reversible type I inhibitor and modulates p-STAT5, p-ERK, SYK, JAK1/2, and TAK1. HM43239 potently inhibits the growth of acute myeloid leukemia cell lines harboring FLT3 ITD mutation. It inhibits MV4-11 (IC50: 1.3 nM), MOLM-13 (IC50: 5.1 nM), and MOLM-14 cells (IC50: 2.9 nM ). HM43239 also inhibits KG1a cells (CD34+/CD38- cells) proliferation. It induces the caspase 3/7-dependent apoptosis of KG1a cells (CD34+/CD38- cells). HM43239 shows the excellent dose-proportional antitumor activity in mouse models xenografted. It includes both MV4-11 and MOLM-13 cell lines without any significant toxicity. HM43239 also prolongs survival in FLT3 ITD/TKD double mutated xenograft mouse models. In summary, HM43239 is a novel FLT3 inhibitor in overcoming resistance for acute myeloid leukemia. Reference: Miyoung Lee, et al. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 804.