Discovery of Dual Function Agents That Exhibit Anticancer Activity via Catastrophic Nicotinamide Adenine Dinucleotide Depletion

Nicotinamide
adenine dinucleotide (NAD) is essentially
involved
in many biological processes of cancer cells, yet chemical intervention
of NAD biosynthesis failed to obtain an optimal therapeutic benefit.
We herein developed a new strategy to induce catastrophic NAD depletion
by concurrently impairing NAD synthesis and promoting NAD consumption.
We designed a series of new compounds that conjugate an inhibitor
of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting
enzyme in the NAD salvage pathway, with a DNA-alkylating agent. Among
them, compound 11b exhibited potent anticancer efficacy
in cancer cell lines and mouse tumor models with intrinsic resistance
to the parent compound FK866 or chlorambucil. Compound 11b caused catastrophic NAD depletion via a synergistic effect between
the NAD salvage pathway blockade and DNA damage-triggered NAD consumption.
Our findings suggest a new intervention strategy for causing catastrophic
NAD depletion in cancer cells and provide basis for the development
of new inhibitors targeting NAD metabolism.