Design of FK866-Based Degraders for Blocking the Nonenzymatic Functions of Nicotinamide Phosphoribosyltransferase

Nicotinamide
phosphoribosyltransferase (NAMPT) is an
attractive
therapeutic target for treating select cancers. There are two forms
of NAMPT: intracellular NAMPT (iNAMPT, the rate-limiting enzyme in
the mammalian NAD+ main synthetic pathway) and extracellular
NAMPT (eNAMPT, a cytokine with protumorigenic function). Reported
NAMPT inhibitors only inhibit iNAMPT and show potent activities in
preclinical studies. Unfortunately, they failed to show efficacy due
to futility and toxicity. We developed a series of FK866-based NAMPT-targeting
PROTACs and identified LYP-8 as a potent and effective
NAMPT degrader that simultaneously diminished iNAMPT and eNAMPT. Importantly, LYP-8 demonstrated superior efficacy and safety in mice when
compared to the clinical candidate, FK866. This study highlights the
importance and feasibility of applying PROTACs as a superior strategy
for interfering with both the enzymatic function of NAMPT (iNAMPT)
and nonenzymatic function of NAMPT (eNAMPT), which is difficult to
achieve with conventional NAMPT inhibitors.