IACS-010759 是一种口服有效的线粒体氧化磷酸化复合物 I (OXPHOS) 抑制剂。IACS-010759 在依赖 OXPHOS 的脑癌和急性髓性白血病 (AML) 模型中抑制增殖并诱导细胞凋亡。IACS-010759 具有用于复发/难治性 AML 和实体瘤研究的潜力。

IACS-010759 hydrochlorideis an orally active, potent mitochondrial complex I of oxidative phosphorylation (OXPHOS) inhibitor. IACS-010759 hydrochlorideinhibits proliferation and induces apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS. IACS-010759 hydrochloride has the potential for relapsed/refractory AML and solid tumors research.

Solid

OXPHOS

IACS-010759 hydrochloride (10, 30, 100?nM; for 4 or 5 days) reduces viability and induces apoptosis in primary AML.
IACS-010759 hydrochloride (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 hydrochlorideis 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 hydrochloride (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.

IACS-010759 hydrochloride (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 QD×5 (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 hydrochloride (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).
has not independently confirmed the accuracy of these methods. They are for reference only.

Room temperature in continental US; may vary elsewhere.

4°C, sealed storage, away from moistur In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

[1]. Protopopova M. IACS-10759: A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Ph
[2]. Jennifer R Molina, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018 Jul;24(7):1036-1046.

In Vitro: DMSO : 60 mg/mL (100.16 mM; Need ultrasonic)H₂O : < 0.1 mg/mL (ultrasonic;warming;heat to 60°C) (insoluble)配制储备液