Nicotinamide phosphoribosyltransferase (NAMPT) serves as the key enzyme in the salvage pathway-mediated biosynthesis of nicotinamide adenine dinucleotide (NAD+), making it a potential target for cancer therapy. However, two significant challenges hinder its successful translation to clinical usage. Firstly, the targeting of the extracellular form of NAMPT (eNAMPT) remains insufficient. Secondly, there are considerable side effects observed in normal tissues, particularly in the hematopoietic system, which relies heavily on the salvage pathway for NAD+ production. In previous research, we utilized proteolysis-targeting chimera (PROTAC) technology to develop two compounds (SIAIS630120 and SIAIS630121) capable of simultaneously degrading iNAMPT and eNAMPT proteins. Unfortunately, the pharmacokinetic properties of these compounds were inadequate for clinical investigation, and toxicity concerns similar to those associated with traditional inhibitors arose. To address these challenges, we have developed a next-generation PROTAC molecule 632005 that demonstrates exceptional target selectivity and bioavailability. This molecule boasts improved in vivo exposure, extended half-life, and reduced clearance rate, positioning it as a highly promising candidate for future clinical applications. Moreover, when combined with nicotinic acid, 632005 successfully exhibits both safety and robust efficacy in the treatment of NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and PDX models with liver cancer. Our findings provide crucial references for patient selection and treatment strategies involving NAMPT-targeting PROTACs in a clinical setting.