ML-162

ML-162 is an inhibitor of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TrxR1).¹ It covalently binds to the GPX4 active site residue selenocysteine 46 (Sec46) and allosteric site residue Cys66 but does not inhibit recombinant human GPX4 activity in a cell-free assay.^2,3,4 ML-162 inhibits TrxR1 in a cell-free assay (IC₅₀ = 19.5 µM) and in A549 cells when used at concentrations ranging from 0.5 to 15 µM.⁴ ML-162 (10 µM) induces the accumulation of cellular lipid hydroperoxides, a marker of ferroptosis, in LOX-IMVI human melanoma cells, an effect that can be blocked by the ferroptosis inhibitor ferrostatin-1 (Item No. 17729).³ It decreases GPX4 levels in MDA-MB-231 breast cancer cells and reduces the viability of BT-549 breast cancer cells, an effect that can be enhanced by α-eleostearic acid (9(Z),11(E),13(E)-octadecatrienoic acid; Item No. 10008349). ML-162 also selectively induces Ras-synthetic lethality in mutant RAS oncogene-expressing cells (IC₅₀s = 25 and 578 nM for HRAS^G12V-expressing and wild-type RAS-expressing BJeH cells, respectively).⁵

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1. Beatty, A., Singh, T., Tyurina, Y.Y., et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12(1), 2244 (2021).

2. Moosmayer, D., Hilpmann, A., Hoffmann, J., et al. Crystal structures of the selenoprotein glutathione peroxidase 4 in its apo form and in complex with the covalently bound inhibitor ML162. Acta Crystallogr. D Struct. Biol. 77(Pt 2), 237-248 (2021).

3. Eaton, J.K., Furst, L., Ruberto, R.A., et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat. Chem. Biol. 16(5), 497-506 (2020).

4. Cheff, D.M., Huang, C., Scholzen, K.C., et al. The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1. Redox Biol. 62, 102703 (2023).

5. Weïwer, M., Bittker, J.A., Lewis, T.A., et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg. Med. Chem. Lett. 22(4), 1822-1826 (2012).

Hendricks, J.M., Doubravsky, C., Wehri, E., et al. Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem. Biol. 30(9), P1090-P1103 (2022).

Li, Z., Ferguson, L., Deol, K.K., et al. Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability. Nat. Chem. Biol. (2022).

Mishima, E., Ito, J., Wu, Z., et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608(7924), 778-783 (2022).

Beatty, A., Singh, T., Tyurina, Y.Y., et al. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1. Nat. Commun. 12(1), 2244 (2021).

Ding, C.-K.C., Rose, J.W., Sun, T., et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat. Metab. 2(3), 270-277 (2020).

Bersuker, K., Hendricks, J., Li, Z., et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784), 688-692 (2019).

Wang, W., Green, M., Choi, J.E., et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569(7755), 270-274 (2019).