Making Protein Degradation Visible: Discovery of Theranostic PROTACs for Detecting and Degrading NAMPT

Proteolysis-targeting chimera (PROTAC) is emerging as a promising technology in targeted protein degradation and drug discovery. However, there is still a lack of effective chemical tools to real-time detect and track the protein degradation. Herein, the first fluorescent and theranostic PROTACs were designed for imaging the degradation of nicotinamide phosphoribosyltransferase (NAMPT) in living cells. Compound B4 was proven to be an environmentally sensitive fluorescent PROTAC, which efficiently degraded NAMPT (DC50 = 8.4 nM) and enabled the visualization of degradation in A2780 cells. As a theranostic agent, PROTAC B4 led to significant reduction of nicotinamide adenine dinucleotide (NAD(+)) and exerted potent antitumor activities both in vitro and in vivo. Collectively, this proof-of-concept study provides a new strategy for the real-time visualization of the process of protein degradation and the improvement of diagnosis and therapeutic efficacy of PROTACs.

Automated summary

Proteolysis-targeting chimera (PROTAC) is a promising technology in targeted protein degradation and drug discovery. This study designed the first fluorescent and theranostic PROTACs for real-time imaging of the degradation of nicotinamide phosphoribosyltransferase (NAMPT) in living cells. The results showed efficient degradation of NAMPT and significant reduction of nicotinamide adenine dinucleotide (NAD(+)), leading to potent antitumor activities in vitro and in vivo. This proof-of-concept study provides a new strategy for real-time visualization of protein degradation and improvement of diagnosis and therapeutic efficacy of PROTACs.