MA191 is an FLT3 PROTAC degrader that effectively addresses FLT3 inhibitor resistance caused by the rebound activation of mitogen-activated kinases. It rapidly degrades FLT3-ITD via a mechanism involving VHL, Neddylation, and BIM, reducing FLT3-ITD levels prior to inducing apoptosis. Moreover, MA191 inhibits the proliferation of AML cells in zebrafish and is applicable for acute myeloid leukemia (AML) research.

MA191 effectively inhibits the growth of MV4-11 and MOLM-13 cells at concentrations ranging from 0-100 nM over a period of 24-72 hours, with an IC50 between 9.6 and 11 nM. At 50 nM for 6-24 hours, MA191 suppresses the autophosphorylation of FLT3 (pY591) and the phosphorylation of ERK1/ERK2, STAT5, and AKT in these cells. In a dose- and time-dependent manner, MA191 (10-50 nM, 16-24 h) reduces the levels of FLT3-ITD and HSP110 in MV4-11 cells. This compound induces BIM-dependent and ubiquitin-like dependent degradation of FLT3-ITD in MV4-11 cells, with DC50 values of 10.5 nM at 16 hours and 10 nM at 24 hours, at concentrations between 0-100 nM for 6-24 hours. Moreover, MA191 (0-1000 nM, 24-48 h) promotes apoptosis in cultured and primary acute myeloid leukemia (AML) cells with FLT3-ITD, without affecting normal immune cells, hematopoietic stem cells, and progenitor cells. It also disrupts the resistance mechanisms of AML cells to FLT3 inhibitors at 50-200 nM over 24-72 hours.

MA191 (200 nM, 48 h, single dose) effectively inhibits acute myeloid leukemia cell proliferation in an in vivo zebrafish larvae model, with no significant toxicity observed.