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

Abstract 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 + .