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HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.The efficient discovery of small-molecule modulators of biomacromolecule function remains a limiting step in target validation and drug discovery. [1] In the conventional procedure for hit compound discovery, iterative cycles of "designsynthesis-screen" are carried out until a potent candidate for further research is obtained. Target-directed dynamic combinatorial chemistry (tdDCC) has been developed as an alternative method for hit identification. [2] tdDCC involves the target-based selection of hits from dynamic mixtures of reversibly reacting compounds (Figure S1). [3] tdDCC can enable the spatially resolved identification of compounds that bind strongly to a defined target protein. [4]