UBCS039

UBCS039 is an activator of sirtuin 6 (SIRT6).¹ It increases the deacetylation of a peptide corresponding to acetylated lysine 9 on histone H3 (H3K9) in a cell-free assay (EC₅₀ = ~38 µM). UBCS039 selectively activates SIRT6 deacetylation activity over SIRT1, SIRT2, and SIRT3 deacetylation activities but does increase SIRT5 desuccinylation activity at 100 µM. It is active against M. tuberculosis (MIC = 50 µM) and is cytotoxic against a panel of six cancer cell lines (IC₅₀s = 9.53-59.25 µM).² UBCS039 (50 mg/kg) decreases disease severity, hepatocyte apoptosis, and aspartate aminotransferase (Ast), alanine transaminase (Alt), IL-1β, IL-6, and TNF-α serum levels in a mouse model of thioacetamide-induced acute liver failure.³ It increases the mean time to thrombotic occlusion in a mouse model of ferric chloride-induced arterial thrombosis when administered at a dose of 2 mg/kg.⁴

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1. You, W., Rotili, D., Li, T.-M., et al. Structural basis of sirtuin 6 activation by synthetic small molecules. Angew. Chem. Int. Ed. Engl. 56(4), 1007-1011 (2017).

2. Makane, V.B., Krishna, E.V., Karale, U.B., et al. Synthesis of novel 4,5-dihydropyrrolo[1,2-a]quinoxalines, pyrrolo[1,2-a]quinoxalin]-2-ones and their antituberculosis and anticancer activity. Arch. Pharm. (Weinheim) 353(12), e2000192 (2020).

3. Jiao, F., Zhang, Z., Hu, H., et al. SIRT6 activator UBCS039 inhibits thioacetamide-induced hepatic injury in vitro and in vivo. Front. Pharmacol. 13, 837544 (2022).

4. Liu, Y., Wang, T., Zhou, Q., et al. Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis. Front. Pharmacol. 14, 1268708 (2023).