AR-C155858 is a novel inhibitor of the monocarboxylate transporters (MCTs) MCT1 and MCT2 (K_i values are 2.3 and < 10="" nm,="" respectively),="" and="" exhibits="" no="" activity="" at="" mct4.="">

Ki: 2.3 nM (MCT1), 10 nM (MCT2)

AR-C155858 (10 nM-100 nM) inhibits MCT1/MCT2 C-terminal chimaeras^[1]. AR-C155858 inhibits MCT2, and the 70% inhibition seen at 10 nM is followed by a gradually increasing inhibition which can only be explained by a K_i value of significantly less than 10 nM. AR-C155858 inhibits MCT1 expressed in Xenopus oocytes in a time- and concentration-dependent manner^[2].

• [1]. Ovens MJ, et al. The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem J. 2010 Oct 15;431(2):217-25.

  [2]. Ovens MJ, et al. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2010 Jan 15;425(3):523-30.

  [3]. Vijay N, et al. A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose. Pharm Res. 2015 Jun;32(6):1894-906.

MCT kinetic assays are performed by monitoring intracellular pH with H⁺-sensitive dye BCECF or by determining the uptake of l-[¹⁴C]lactate (7.4 MBq/mL). The uptake buffer containes 75 mM NaCl, 2 mM KCl, 0.82 mM MgCl₂, 1 mM CaCl₂ and 20 mM Tris/Hepes (pH 7.4). AR-C155858 inhibitor titrations are performed at pH 6 with oocytes preincubated for 45 min in a different uptake buffer (75 mM NaCl, 2 mM KCl, 0.82 mM MgCl₂, 1 mM CaCl₂ and 20 mM Mes, pH 6) containing the required concentration of AR-C155858 prior to measuring the uptake of l-[¹⁴C]lactate (0.5 mM). Unless stated otherwise, uptake is determined over 2.5 min for all MCT constructs except for MCT2trn with or without embigin and MCT2/1 with or without embigin, where 5 and 10 min are used respectively. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

AR-C155858 is dissolved in DMSO.

The erythrocytes (5% haematocrit) are pre-incubated for 1 h at room temperature (22°C) with or without AR-C155858 at the required concentration before assaying transport of l-lactate (10 mM) at 6°C. Initial rates of transport are calculated by first-order regression analysis of the time course of pH change and converted into nmol of H⁺/min by determining the pH change induced by small additions of standardized NaOH. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Ovens MJ, et al. The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem J. 2010 Oct 15;431(2):217-25.

  [2]. Ovens MJ, et al. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2010 Jan 15;425(3):523-30.

  [3]. Vijay N, et al. A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose. Pharm Res. 2015 Jun;32(6):1894-906.

461.53

C₂₁H₂₇N₅O₅S

496791-37-8

Room temperature in continental US; may vary elsewhere

10 mM in DMSO

AR-C155858 is prepared as a 2.5 mg/mL solution in 10% cyclodextrin in normal saline^[3].

* "<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">

• [1]. Ovens MJ, et al. The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem J. 2010 Oct 15;431(2):217-25.

  [2]. Ovens MJ, et al. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2010 Jan 15;425(3):523-30.

  [3]. Vijay N, et al. A Novel Monocarboxylate Transporter Inhibitor as a Potential Treatment Strategy for γ-Hydroxybutyric Acid Overdose. Pharm Res. 2015 Jun;32(6):1894-906.