Discovery of a Potent NAMPT-Targeting PROTAC for the Suppression of Triple-Negative Breast Cancer via Macrophage Reprogramming.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in NAD+ salvage pathway and a promising therapeutic target for triple-negative breast cancer (TNBC). However, the clinical efficacy of current NAMPT inhibitors remains limited. Herein, we designed and synthesized a series of NAMPT-targeting proteolysis-targeting chimeras (PROTACs) using OT-82 as the warhead. Compound A13 was identified as a potent NAMPT degrader, with DC50 values of 9.31 ± 1.65 nM in MDA-MB-231 cells and 12.54 ± 3.36 nM in 4T1 cells. A13 significantly suppressed the proliferation, migration and invasion of TNBC cells, and modulated the tumor microenvironment by promoting tumor-associated macrophages (TAMs) polarization toward an M1-like phenotype. In orthotopic TNBC allograft models, A13 achieved significant tumor growth inhibition (TGI = 82.7%) without obvious toxicity and effectively suppressed lung metastasis. These results demonstrate that NAMPT degradation suppresses primary tumor growth and lung metastasis in TNBC, offering a promising lead compound and therapeutic strategy.