Discovery of Highly Potent Nicotinamide Phosphoribosyltransferase Degraders for Efficient Treatment of Ovarian Cancer

Nicotinamide phosphoribosyltransferase (NAMPT) is identified
as
a promising target for cancer therapy. However, known NAMPT inhibitors
are characterized by weak clinical efficacy and dose-dependent toxicity.
There is an urgent need to develop new NAMPT intervention strategies.
Using the proteolysis-targeting chimera (PROTAC) technology, we designed
and synthesized a series of new von Hippel-Lindau (VHL)-recruiting
NAMPT-targeting PROTACs. A highly potent NAMPT degrader (B3) was successfully identified, which displayed excellent degradation
activity (DC50 < 0.17 nM, Dmax > 90%) and antiproliferative potency against A2780 cells (IC50 = 1.5 nM). PROTAC B3 induced NAMPT depletion
in a concentration- and time-dependent manner through the ubiquitin-proteasome
system. Particularly, PROTAC B3 achieved good plasma
exposure levels via intravenous injection, gained potent tumor growth
inhibition (TGI = 88.1%, 2 μM/kg) in the xenograft model, and
demonstrated good biosafety without undesired toxicities. This study
provides a highly potent VHL-recruiting NAMPT degrader for the treatment
of ovarian cancer.