Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD), making it a potential target for cancer therapy. Two challenges hinder its translation in the clinic: targeting the extracellular form of NAMPT (eNAMPT) remains insufficient, and side effects are observed in normal tissues. We previously utilized proteolysis-targeting chimera (PROTAC) to develop two compounds capable of simultaneously degrading iNAMPT and eNAMPT. Unfortunately, the pharmacokinetic properties were inadequate, and toxicities similar to those associated with traditional inhibitors arose. We have developed a next-generation PROTAC molecule 632005 to address these challenges, demonstrating exceptional target selectivity and bioavailability, improved exposure, extended half-life, and reduced clearance rate. When combined with nicotinic acid, 632005 exhibits safety and robust efficacy in treating NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and patient-derived xenograft (PDX) models with liver cancer. Our findings provide clinical references for patient selection and treatment strategies involving NAMPT-targeting PROTACs.

中文翻译：

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靶向 NAMPT 的 PROTAC 和烟酸联合给药在 NAPRT 缺陷的泛癌中产生安全而强大的抗肿瘤功效


烟酰胺磷酸核糖转移酶（NAMPT）催化烟酰胺腺嘌呤二核苷酸（NAD）的生物合成，使其成为癌症治疗的潜在靶点。两个挑战阻碍了其在临床上的转化：针对细胞外形式的 NAMPT (eNAMPT) 仍然不足，并且在正常组织中观察到副作用。我们之前利用蛋白水解靶向嵌合体 (PROTAC) 开发了两种能够同时降解 iNAMPT 和 eNAMPT 的化合物。不幸的是，药代动力学特性不足，并且出现了与传统抑制剂类似的毒性。我们开发了下一代 PROTAC 分子 632005 来应对这些挑战，表现出卓越的靶点选择性和生物利用度、改善的暴露、延长的半衰期和降低的清除率。当与烟酸联合使用时，632005 在治疗 NAPRT 缺陷的泛癌方面表现出安全性和强大的功效，包括患有血液恶性肿瘤和前列腺癌的异种移植模型以及患有肝癌的患者来源的异种移植（PDX）模型。我们的研究结果为涉及 NAMPT 靶向 PROTAC 的患者选择和治疗策略提供了临床参考。