KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.

中文翻译：

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抗肿瘤 NAMPT 抑制剂 KPT-9274 通过调节 SIRT3 介导的 SOD 去乙酰化作用来介导性别依赖性小鼠贫血和肾毒性

KPT-9274 是针对实体瘤和非霍奇金淋巴瘤的 1 期首创双重 PAK4/NAMPT 抑制剂。它通过抑制 NAMPT 依赖性 NAD+ 的产生，证明了对广谱急性髓性白血病 (AML) 亚型的临床前疗效。NAMPT 是导致 NAD+ 生成的补救代谢途径中的限速酶。缺乏从头途径酶 NAPRT1 的肿瘤细胞对 NAMPT 上瘾。在临床试验中，使用 NAMPT 抑制剂治疗会导致剂量限制性毒性。为了剖析毒性机制，用 KPT-9274 处理小鼠，并对由此产生的毒性进行组织病理学和生物化学表征。KPT-9274 治疗会导致性别相关的胃和肾损伤和贫血。用 KPT-9274 治疗的雌性小鼠有 EPO 缺乏和相关的红细胞生成受损。KPT-9274 治疗抑制 SIRT3 表达并同时上调 IMCD3 细胞中的乙酰锰超氧化物歧化酶 (MnSOD)，为观察到的肾毒性提供了机制基础。重要的是，烟酸补充剂减轻了 KPT-9274 引起的肾损伤和 EPO 缺乏，而不影响其功效。总之，我们的研究描述了 KPT-9274 介导的毒性机制，并阐明了开发策略以提高这种重要的抗 AML 抑制剂的耐受性。烟酸补充剂减轻了 KPT-9274 引起的肾损伤和 EPO 缺乏，而不影响其疗效。总之，我们的研究描述了 KPT-9274 介导的毒性机制，并阐明了开发策略以提高这种重要的抗 AML 抑制剂的耐受性。烟酸补充剂减轻了 KPT-9274 引起的肾损伤和 EPO 缺乏，而不影响其疗效。总之，我们的研究描述了 KPT-9274 介导的毒性机制，并阐明了开发策略以提高这种重要的抗 AML 抑制剂的耐受性。