AT-406 (SM-406)

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Background

K(i): The Ki of XIAP, cIAP1, and cIAP2 proteins is 66.4, 1.9, and 5.1 nM, respectively.AT-406 is alsonamed as SM-406. AT-406 is a potent and orally bioavailable antagonist of multiple inhibitor of apoptosis proteins (IAPs). The inhibitor of apoptosis proteins(IAPs), originally identified in baculoviruses,are a family of apoptosis suppressor proteins which could bind and inhibit specific enzymes (caspases) such as caspase 3, 7, and 9, but not caspase 8 [1]. Growing evidence has showed that IAPs can regulateprogrammed cell death, apoptosis, cell division, cell cycle progression, and signal transduction pathways [1].In vitro: The Ki of AT-406 against XIAP, cIAP1, and cIAP2 proteins is 66.4, 1.9, and 5.1 nM, respectively[2]. In human ovarian cancer cell lines, treatment with AT-406 for 48h could dose-dependently activate the apoptotic pathway. IC50 values of AT-406 in these ovarian cancer cells range from 0.05-0.5 μg/ml [3]. AT-406 could sensitize the response of ovarian cancer cells to carboplatin, a standard first-line chemotherapy for ovarian cancer [2]. In vivo: AT-406 exhibited good oral bioavailability in the mouse, rat, dog and non-human primates. In Rag-1 mice bearing intraperitoneally implanted OVCAR-3ip cells, AT-406 (100 mg/kg by oral gavage) significantly inhibited the progression of ovarian cancer and prolonged survival of the experimental mice both in single agent and in combination with carboplatin (40 mg/kg intraperitoneal injection) [2]. In xenograft mouse model of human breast cancer, 2-week treatment with 30 mg/kg or 100 mg/kg AT-406 effectively delayed the tumor growth [3].Clinical trial: Oral treatment of AT-406 daily on days 1-5, initially every 14 days, later every 21 days was well tolerated at doses up to 900 mg in patients with different cancer types (Hurthle cell, melanoma, breast, rectal, hemangiopericytoma) [4].

Schimmer A D. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice[J]. Cancer research, 2004, 64(20): 7183-7190.
Cai Q, Sun H, Peng Y, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment[J]. Journal of medicinal chemistry, 2011, 54(8): 2714-2726.
Zhang T, Li Y. et al. APhysiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos. 2013 Sep;34(6):348-59.
Hurwitz HI1, Smith DC, et al. Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Cancer ChemotherPharmacol. 2015 Apr;75(4):851-9.