Design of Photoaffinity Probe Molecules for Identification and Modification of Target Proteins

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Techniques for the visualization of target proteins by small-molecule probes in living systems are highly important to investigate the function, dynamics, localization, and crosstalk of individual proteins. We have studied inhibitors of hypoxia-inducible factors (HIF), which are heterodimeric (α/β) transcriptional factors and major physiological stimuli for expression of angiogenesis factors. Inhibition of tumor-induced angiogenesis prevents growth of many types of solid tumors, thus is considered to provide a novel approach for cancer treatment. We recently developed carborane-containing phenoxyacetanilides as potent inhibitors of HIF-1α activation under hypoxia. We designed their photoaffinity labeling molecules to clarify the action mechanism against the HIF inhibition. Using the photoaffinity labeling molecules, we identified that heat shock protein (HSP) 60 is the target protein and clarified that HSP60 has an important role for stabilization of HIF-1α under hypoxia.

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