AA147

AA147 is an endoplasmic reticulum (ER) proteostasis regulator.^1,2,3 It activates an activating transcription factor 6-dependent (ATF6-dependent) ER stress response element reporter and antioxidant response element reporter in HT22 hippocampal cells (EC₅₀s = 3.6 and 3.92 µM, respectively) and protects against glutamate-induced cytotoxicity and prevents increases in reactive oxygen species (ROS) in HT22 cells when used at a concentration of 10 µM.¹ AA147 (10 µM) reduces cell death induced by the unfolded protein response (UPR) activator tunicamycin and increases ER-associated protein degradation (ERAD) in neonatal rat ventricular myocytes.² It reduces the myocardial, renal, and cerebral infarct size as a percentage of the area at risk in mouse models of ischemia-reperfusion injury induced by left anterior descending coronary artery (LAD) ligation, renal portal system occlusion, or middle cerebral artery occlusion (MCAO), respectively, when administered at a dose of 2 mg/kg. AA147 also prevents the production of non-structural protein 5 (NS5) in dengue virus-infected Huh7 cells (IC₅₀ = ~1 µM).³

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1. Rosarda, J.D., Baron, K.R., Nutsch, K., et al. Metabolically activated proteostasis regulators protect against glutamate toxicity by activating NRF2. ACS Chem. Biol. 16(12), 2852-2863 (2021).

2. Blackwood, E.A., Azizi, K., Thuerauf, D.J., et al. Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis. Nat. Commun. 10(1), 187 (2019).

3. Almasy, K.M., Davies, J.P., Lisy, S.M., et al. Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections. Proc. Natl. Acad. Sci. USA 118(3), e2012209118 (2021).