As chemists at a medical center, we are integrating newly developed chemical methods into medicinal chemistry programs. We have discovered isoform-selective inhibitors of novel targets for the treatment of cancer.
For example, we have developed an enantioselective cycloaddition for the synthesis of an isoform-selective inhibitor (Kd=80 nM) of hypoxia inducible factor 2α, a key component in the deregulated growth and remodeled metabolism of cancer cells.
We have also designed new methods to access an isoform-selective chiral inhibitor (Kd=250 nM) of pyruvate dehydrogenase kinase 2, which plays an essential role in tumor-specific metabolic remodeling.
The pharamocokinetic analysis of these inhibitors is guiding future research directions, as we transition into studying biological activity in animal models.