ML-210

ML-210 is a prodrug inhibitor of GPX4 and an inducer of ferroptosis.¹ ML-210 forms adducts with GPX4 in cells and inhibits GPX4 enzymatic activity in cell lysates but does not form adducts with recombinant human GPX4 or bind to GPX4 in a lysate-based cellular thermal shift assay (CETSA^®) or a pull-down assay, indicating that a cellular transformation is required for its activity.^1,2 In cells, ML-210 is converted to an active metabolite, JKE-1674 (Item No. 30784), which is then converted to a second active metabolite, JKE-1777.¹ ML-210 (10 µM) induces the accumulation of cellular lipid hydroperoxides in LOX-IMVI human melanoma cells, an effect that can be blocked by the ferroptosis inhibitor ferrostatin-1 (Item No. 17729).¹ It also induces ferroptotic cell death in LNCaP and androgen-independent LNCaP (LNCaP-AI) human prostate cancer cells, an effect that can be blocked by the ferroptosis inhibitors ferrostatin-1 or liproxstatin-1 (Item No. 17730).³ ML-210 selectively induces Ras-synthetic lethality in mutant RAS oncogene-expressing cells (IC₅₀s = 71 and 272 nM in HRAS^G12V-expressing and wild-type RAS-expressing BJeH human fibroblasts, respectively).^4,5

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1. 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).

2. 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).

3. Zhao, R., Lv, Y., Feng, T., et al. ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis. Prostate 82(5), 617-629 (2022).

4. 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).

5. Viswanathan, V.S., Ryan, M.J., Dhruv, H.D., et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547(7664), 453-457 (2017).

Nakamura, T., Hipp, C., Mourão, A.S.D., et al. Phase separation of FSP1 promotes ferroptosis. Nature 619, 371-377 (2023).

Xue, Q., Yan, D., Chen, X., et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy (2023).

­Wang, F., Graham, E.T., Naowarojna, N., et al. PALP: A rapid imaging technique for stratifying ferroptosis sensitivity in normal and tumor tissues in situ. Cell Chem. Bio. 29, 157-170 (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).

Nagakannan, P., Islam, M.I., Conrad, M., et al. Cathepsin B is an excutioner of ferroptosis. Biochim. Biophys. Acta Mol. Cell Res. 1868(3), 118928 (2021).

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