TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax
We identified activin A receptor type I (ACVR1), part of the TGF-ß superfamily, like a factor favoring acute myeloid leukemia (AML) growth along with a new potential therapeutic target. ACVR1 is overexpressed in FLT3-mutated AML and inhibition of ACVR1 expression sensitized AML cells to FLT3 inhibitors. We created a novel ACVR1 inhibitor, TP-0184, which selectively caused growth arrest in FLT3-mutated AML cell lines. Molecular docking as well as in vitro kinase assays says TP-0184 binds to both ACVR1 and FLT3 rich in affinity and inhibits FLT3/ACVR1 downstream signaling. Treatment with TP-0184 or in conjunction with BCL2 inhibitor, venetoclax dramatically inhibited leukemia development in FLT3-mutated AML cell lines and patient-derived xenograft models inside a dose-dependent manner. These bits of information claim that ACVR1 is really a novel biomarker and plays a part in AML potential to deal with FLT3 inhibitors which FLT3/ACVR1 dual inhibitor TP-0184 is really a novel potential therapeutic tool for AML with FLT3 mutations.