TLK117

TLK117, the active metabolite of TLK199, selective inhibits Glutathione S-transferase P1-1 (GSTP1-1) with a K_i of 0.4 μM for GSTP. TLK117 also competitively inhibits glyoxalase I with a K_i of 0.56 μM. IC50 & Target:Ki: 0.4 μM^[1], 0.56 μM (glyoxalase I)^[2] In Vitro: TLK117 is the most specific GSTP inhibitor to date, with a binding affinity greater than GSH itself and a selectivity for GSTP over 50-fold greater than the GSTM and GSTA classes (K_i=0.4 μM)^[1]. TER 117 is developed as a GST P1-1 isoenzyme inhibitor to circumvent the indicated contribution of GST P1-1 to drug resistance of tumor cells. To facilitate the cellular uptake of TER 117, it is delivered as a diethyl ester (TER 117 DEE, also called TER 199). TER 117 is found to be a competitive inhibitor of both GST P1-1 and glyoxalase I^[2]. In Vivo: Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis is already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. Four hours after administration of 50 mg/kg TLK117, GSTP activity is strongly decreased and remains decreased by about 60% for at least 24 hours^[2].