IACS-010759 hydrochloride is an orally potent and selective OXPHOS inhibitor that inhibits proliferation and induces apoptosis in OXPHOS-dependent brain cancer and acute myeloid leukaemia models for the study of relapsed/refractory AML and advanced solid tumours.

Mitochondrial oxidative phosphorylation (Rat primary cells):12.2 nM, Mitochondrial oxidative phosphorylation (H460 cells):1.4 nM (72 h), Mitochondrial oxidative phosphorylation (Mouse primary cells):5.6 nM, Mitochondrial oxidative phosphorylation (Cynomolgus monkey primary cells):8.7 nM, Mitochondrial oxidative phosphorylation (AML patient-derived cells):10-100 nM (4-5 days)

IACS-010759 hydrochloride shows potent in vitro activity by reducing AML cell viability and inducing apoptosis at concentrations of 10-100 nM over 4-5 days. It also inhibits mitochondrial OCR and oxidative phosphorylation-dependent viability in H460 cells, with an average IC₅₀ of 1.4 nM over 72 h. Similar potency was observed in cells from mice (IC₅₀ = 5.6 nM), rats (12.2 nM), and cynomolgus monkeys (8.7 nM)[1].

In NB-1 neuroblastoma xenograft mice, oral IACS-010759 hydrochloride at 5-10 mg/kg for 21 days significantly reduced tumor size, although 25 mg/kg was not well tolerated. In another model, daily or alternate-day dosing at 10 mg/kg for 35 days extended survival from 28 to over 60 days, and lower-frequency dosing (e.g., 2×/week) also improved outcomes. Pharmacokinetic studies showed that a 0.3 mg/kg dose had low clearance, limited distribution, and a prolonged half-life (>24 h)[1].