ABD778 is a potent and selective, in vivo-active ABHD17 inhibitor with IC50 of 76 nM and 84 nM for both human and mouse ABHD17 enzymes, respectively, is the isopropyl ester analog of ABD957.
ABD778 demonstrates high specificity for ABHD17 enzymes across the detectable serine hydrolases in both mouse and human proteomes.
ABD778 potently inhibits all ABHD17 isoforms in OCI-AML3 cells while maintaining a similar selectivity profile as observed in cell lysates.
ABD778 selectively reduces the growth of NRAS-mutant leukemia cells and is synergistic with PD901 in vitro.
ABD778 significantly reduced both cytokine-independent and GM-CSF-stimulated colony growth of JMML cells with NRAS mutations but had no effect on KRAS-mutant cells.
ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib, the K/N-RasG12C inhibitor sotorasib, and the FLT3 inhibitor gilteritinib in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition.