SRI-37330 (SRI 37330) is an orally available small molecule that regulates TXNIP expression, inhibits endogenous TXNIP mRNA expression (IC50=0.64 uM, INS-1 cells qRT-PCR assays).
SRI-37330 inhibited the activity of the human TXNIP promoter in INS-1 cells by 70% and no cytotoxicity, significantly inhibited TXNIP expression in rat INS-1 cells, primary mouse islets, and isolated human islets.
SRI-37330 significantly changed TXNIP-associated genes, upregulated CTGF, BCL2L1, IGF1R and MAFA, downregualted NLRP1 and MLXIPL, in INS-1 cells.
SRI-37330 effectively inhibited polymerase II (Pol II) binding to the E-box motif region of the TXNIP promoter, but not to an upstream TXNIP promoter region or to an established Pol II binding site in the insulin receptor substrate 2 (IRS2).
SRI-37330 lowers serum glucagon levels, inhibits hepatic glucose production and improves glucose homeostasis in mice (100 mg/kg/day in the drinking water).