Ispinesib as an Effective Warhead for the Design of Autophagosome-Tethering Chimeras: Discovery of Potent Degraders of Nicotinamide Phosphoribosyltransferase (NAMPT)

Autophagosome-tethering
compounds (ATTECs) are an emerging new
technology in targeted protein degradation. However, effective tools
and successful examples for autophagosome-tethering chimeras are still
rather limited. Herein, ATTEC ispinesib was identified for the first
time to be an effective warhead to design autophagosome-tethering
chimeras. As a conceptual validation study, the first generation of
autophagic degraders of nicotinamide phosphoribosyltransferase (NAMPT)
were developed by connecting the NAMPT inhibitor and LC3-binding ispinesib
through a flexible linker. In particular, compound A3 significantly induced the degradation of NAMPT through the autophagy-lysosomal
pathway, leading to excellent cellular antitumor potency. Ispinesib
may have broad applications in the design of potent autophagosome-tethering
chimeras.