ML-228

The hypoxia-inducible factor (HIF) transcription factors are members of the basic-helix-loop-helix (bHLH) family of transcription factors and play important roles in maintaining cellular oxygen homeostasis.^1,2 HIF-1α has emerged as an important drug target in breast and prostate cancer, cardiovascular disease, and ischemia.^3,4 ML-228 is an activator of the HIF signaling pathway, as demonstrated by HIF response element (HRE) reporter assay (EC₅₀ = 1.2 µM), HIF-1α nuclear translocation assay (EC₅₀ = 1.3 µM), and increased VEGF expression (EC₅₀ = 1.6 µM).⁵ Its activity in the HRE assay is blocked by excess iron, suggesting that ML-228 can chelate iron.⁵ Molecular modeling indicates that ML-228 does not modulate HIF signaling by binding to prolyl hydroxyases.⁵ ML-228 also significantly inhibits ligand binding to several channels, receptors, and transporters, including ERG potassium channel, 5-HT_2B and A₃ adenosine receptors, and dopamine transporter.⁵

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1. Wang, G.L., Jiang, B.H., Rue, E.A., et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension. Proc. Natl. Acad. Sci. USA 92(12), 5510-5514 (1995).

2. Safran, M., and Kaelin, W.G., Jr. HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin. Invest. 111(6), 779-783 (2003).

3. William, C., Masson, N., Tian, Y.M., et al. Peptide blockade of HIFα degradation modulates cellular metabolism and angiogenesis. Proc. Natl. Acad. Sci. USA 99(16), 10423-10428 (2002).

4. Welsh, S., Williams, R., Kirkpatrick, L., et al. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1α. Mol. Cancer Ther. 3(3), 233-244 (2004).

5. Theriault, J.R., Felts, A.S., Bates, B.S., et al. Discovery of a new molecular probe ML228: An activator of the hypoxia inducible factor (HIF) pathway. Bioorg. Med. Chem. Lett. 22(1), 76-81 (2012).