Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD⁺ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD⁺ reserve. NAD⁺ depletion may be a promising alternative approach to treating patients with B-ALL.

中文翻译：

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针对B细胞急性淋巴细胞白血病中NAD +耗竭的脆弱性。

尽管在治疗B细胞急性淋巴细胞白血病（B-ALL）方面已取得实质性进展，但是顽固性或复发性B-ALL患者的预后仍然不佳。需要新的治疗策略来改善这些患者的预后。KPT-9274是p21活化激酶4（PAK4）和烟酰胺磷酸核糖基转移酶（NAMPT）的新型双重抑制剂。PAK4是一种调节各种基本细胞过程的丝氨酸/苏氨酸激酶。NAMPT是烟酰胺腺嘌呤二核苷酸（NAD）抢救生物合成途径中的限速酶，在能量代谢中起着至关重要的作用。在这里，我们显示KPT-9274强烈抑制B-ALL细胞的生长，无论其细胞遗传学异常如何。我们还证明了在来自患者的B-ALL异种移植小鼠模型中，KPT-9274的有效体内功效和耐受性。有趣的是，尽管KPT-9274是PAK4 / NAMPT双重抑制剂，但补充烟碱酸可消除KPT-9274对B-ALL细胞生长的抑制作用，这表明对B-ALL细胞的抑制作用主要是由NAD发挥的。⁺通过NAMPT抑制而耗竭。此外，我们发现B-ALL细胞对NAMPT抑制的极易感性与细胞NAD ⁺储备的减少有关。NAD ⁺耗竭可能是治疗B-ALL患者的有前途的替代方法。