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

Area of Science:

• Biochemistry
• Oncology
• Medicinal Chemistry

Background:

• Nicotinamide adenine dinucleotide (NAD) is crucial for cancer cell biology.
• Previous attempts to inhibit NAD biosynthesis for cancer therapy yielded limited success.

Purpose of the Study:

• To develop a novel strategy for inducing catastrophic NAD depletion in cancer cells.
• To design and evaluate compounds that inhibit NAD synthesis and promote NAD consumption concurrently.

Main Methods:

• Conjugation of a NAMPT inhibitor with a DNA-alkylating agent to create novel compounds.
• Evaluation of compound efficacy in cancer cell lines and mouse tumor models.
• Assessment of NAD depletion mechanisms, including synergistic effects.

Main Results:

• Compound 11b demonstrated significant anticancer efficacy against resistant cancer models.
• Compound 11b induced catastrophic NAD depletion through a synergistic mechanism.
• The synergistic effect involved simultaneous blockade of the NAD salvage pathway and DNA damage-induced NAD consumption.

Conclusions:

• A novel therapeutic strategy targeting NAD metabolism by dual inhibition of synthesis and promotion of consumption is effective.
• Compound 11b shows promise as an anticancer agent, overcoming resistance to existing therapies.
• This research provides a foundation for developing new drugs targeting NAD metabolism in cancer treatment.