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Biological Activity:
ML228 is a hypoxia inducible factor (HIF) pathway activator with an EC₅₀ at ~1.23 µM in HRE gene reporter assay and ~1.4 μM in HIF-1α nuclear translocations assay. It does not inhibit the proteasome, but activates HIF stabilization and nuclear translocations, and induces expression of a HIF specific downstream gene (VEGF). It has no apparent toxicity below 30 μM and appeared to be an iron chelator, independently of PHD. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. HIF pathway is the most significant pathway for cellular response to hypoxia.