The global burden of breast cancer remains formidable, as current therapeutic regimens frequently fail to achieve optimal outcomes. A growing body of evidence supports targeting nicotinamide adenine dinucleotide (NAD) metabolism—a molecule indispensable to the viability and expansion of malignant cells—as a compelling anticancer strategy. In mammalian systems, maintaining adequate NAD pools depends on two principal enzymes: nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymerase 1 (PARP1). Recent investigations have drawn attention to the potential therapeutic gain from pairing NAMPT inhibitors with PARP1 inhibitors, particularly for breast cancer. In the present study, a series of eleven unprecedented NAMPT/PARP1 dual-target inhibitors was conceived and prepared. One analog, designated DDY02, displayed tolerable potency against both enzymatic targets, registering IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro profiling demonstrated that exposure to DDY02 triggered suppressed cell growth, NAD diminution, DNA lesions, programmed cell death, and reduced migratory capacity in MDA-MB-468 cells. Collectively, these data position DDY02—acting on NAD metabolism by concurrently blocking NAMPT and PARP1—as a promising lead structure for breast cancer treatments.
