IACS-010759

IACS-010759 (IACS010759) is a small molecule inhibitor of mitochondrial oxidative phosphorylation (OXPHOS), targets complex I of the mitochondrial electron transport chain; decreases cell viability and increases apoptosis with EC50 values between 1 nM-50 nM across multiple lines; robustly inhibits proliferation and induces apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, reduces aspartate production that leads to impaired nucleotide biosynthesis; potently inhibits tumor growth of brain cancer and AML in vivo.Blood Cancer Phase 1 Clinical (In Vitro) :IACS-010759 (10, 30, 100 nM; for 4 or 5 days) reduces viability and induces apoptosis in primary AML.IACS-010759 (0.001, 0.01, 0.1, 1, 10, 100, 1000 nM; 72 hurs) robustly inhibits both OCR and galactose-dependent H460 cell viability and has nearly identical IC50 values of 1.4 nM.IACS-010759 is similarly active in mouse (average IC50 = 5.6 nM), rat (IC50 = 12.2 nM), and cynomolgus monkey (IC50 = 8.7 nM) cell lines.IACS-010759 (0.01-10 μM) yieldes a maximal reduction of growth of > 50% in the majority of cancer cell lines (24 of 30 pancreatic (PDAC), 19 of 20 ovarian, 13 of 16 triple-negative breast (TNBC), 8 of 10 non-small-cell lung (NSCLC) ) and a subset (11of 30 PDAC, 10 of 20 ovarian, 5 of 16 TNBC, 2 of 10 NSCLC) exhibited > 100% growth inhibition. (In Vivo) :IACS-010759 (5, 10, 25 mg/kg/day; oral; for 21 d) results in tumor regression with minimal body weight loss at the 5 or 10 mg/kg dose in mice bearing NB-1 (PGD-null) subcutaneous xenografts. IACS-010759 at the 25 mg/kg dose is not tolerated.IACS-010759 HCl (10 mg/kg; orally; QD (daily) or QDx5 (5 d on/2 d off) ; for 35 d) increases median survival from 28 d to longer than 60 d, whereas less-frequent dosing schedules (Q2D or Q3D) enhances survival to a lesser extent.IACS-010759 (0.3 mg/kg for iv; 1 mg/kg for oral) has low plasma clearance with a high volume of distribution, resulting in a prolonged terminal half-life (>24 h) .