ML228 (ML-228; CID-46742353) is an activator of the Hypoxia Inducible Factor (HIF) which potently activate HIF in vitro as well as its downstream target VEGF. Hypoxia and ischemia are related to numerous public health problems affecting most major organ systems. Examples include the cardiovascular, pulmonary, renal, neurologic, and musculoskeletal systems. Furthermore, angiogenesis is required for tissue repair and regeneration. In cases of ischemia, whether due to injury or disease, enhancing blood supply is a common goal. The most significant pathway for cellular response to hypoxia is the hypoxia inducible factor (HIF) pathway. HIFs are transcription factors responsible for the activation of genes which encode proteins that mediate adaptive responses to reduced oxygen availability. The molecular probe ML228 demonstrated activity in a cell-based HIF-mediated gene reporter assay with an EC50 around 1 μM. This probe did not inhibit the proteasome, activated HIF stabilization and nuclear translocation, and induced expression of a HIF specific downstream gene (VEGF). It had no apparent toxicity below 30 μM and appeared to be an iron chelator.

References: Bioorg Med Chem Lett. 2012 Jan 1;22(1):76-81; Probe Reports from the NIH Molecular Libraries Program.