ABD778

ABD778 is a small molecule inhibitor of ABHD17 serine hydrolases, designed to disrupt the N-Ras palmitoylation cycle. By inhibiting the depalmitoylation of N-Ras, ABD778 causes the mis-localization of the protein, thereby selectively impairing the growth of NRAS-mutant acute myeloid leukemia (AML) cells. Developed as a more pharmacologically optimized analog of the tool compound ABD957, ABD778 has demonstrated nanomolar potency and sustained in vivo target engagement. Preclinical studies indicate that ABD778 acts synergistically with MEK inhibitors, such as PD0325901, to suppress ERK and S6 phosphorylation and prolong survival in mouse models of NRAS-mutant AML.