Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD⁺

Nicotinamide adenine dinucleotide (NAD(+)) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme involved in NAD(+) biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD(+) in biological systems using photoswitchable proteolysis-targeting chimeras (PS-PROTACs). An NAMPT activator and dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS-PROTACs, enabling up- and down-reversible regulation of NAMPT and NAD(+) in a light-dependent manner and reducing the toxicity associated with inhibitor-based PS-PROTACs. PS-PROTAC was activated under 620 nm irradiation, realizing in vivo optical manipulation of antitumor activity, NAMPT, and NAD(+).