GMX1778 (CHS828) is a specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT)[1]. NAD+ (Nicotinamide Adenine Dinucleotide) is a key coenzyme found in all living cells, playing an important role in cellular energy metabolism and redox reactions[2]. GMX1778 blocks the biosynthesis of NAD+ and decreases intracellular NAD+ levels by inhibiting the activity of NAMPT, which in turn causes ATP depletion and ultimately induces apoptosis-like programmed cell death[3]. GMX1778 is commonly used in cancer-related research[4].
In vitro, GMX1778 (30nM-1µM; 24h) significantly depleted intracellular NAD+ levels and induced cytotoxicity in HT1080 cells[5]. GMX1778 (5nM; 48h) significantly increased intracellular reactive oxygen species (ROS) levels and led to apoptosis in NAPRT1-negative cancer cells such as U251 and MDA-MB-231BR[6].
In vivo, GMX1778 (100mg/kg/week; 3 weeks; oral gavage) significantly enhanced the antitumor effect of 177Lu-DOTATATE treatment, prolonged the median time to tumor progression and reduced tumor volume in a neuroendocrine tumor (NET) xenograft mice model[7].
References:
[1] Watson M, Roulston A, Bélec L, et al. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol. 2009;29(21):5872-5888.
[2] Zapata-Perez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. NAD+ homeostasis in human health and disease. EMBO Mol Med. 2021;13(7):e13943.
[3] Olesen UH, Christensen MK, Björkling F, et al. Anticancer agent CHS-828 inhibits cellular synthesis of NAD. Biochem Biophys Res Commun. 2008;367(4):799-804.
[4] Ekelund S, Nygren P, Larsson R. Guanidino-containing drugs in cancer chemotherapy: biochemical and clinical pharmacology. Biochem Pharmacol. 2001;61(10):1183-1193.
[5] Guo J, Lam LT, Longenecker KL, et al. Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation. Biochem Biophys Res Commun. 2017;491(3):681-686.
[6] Cerna D, Li H, Flaherty S, Takebe N, Coleman CN, Yoo SS. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) activity by small molecule GMX1778 regulates reactive oxygen species (ROS)-mediated cytotoxicity in a p53- and nicotinic acid phosphoribosyltransferase1 (NAPRT1)-dependent manner. J Biol Chem. 2012;287(26):22408-22417.
[7] Elf AK, Bernhardt P, Hofving T, et al. NAMPT Inhibitor GMX1778 Enhances the Efficacy of 177Lu-DOTATATE Treatment of Neuroendocrine Tumors. J Nucl Med. 2017;58(2):288-292.
GMX1778 (CHS828) 是一种特异性的烟酰胺磷酸核糖转移酶（NAMPT）抑制剂[1]。NAD+（烟酰胺腺嘌呤二核苷酸）是一种存在于所有活细胞中的关键辅酶，在细胞能量代谢和氧化还原反应中发挥着重要作用[2]。GMX1778通过抑制NAMPT的活性，阻碍NAD+的生物合成，降低细胞内NAD+水平，进而引起ATP耗竭，最终诱导具有凋亡特征的程序性细胞死亡[3]。GMX1778通常用于癌症相关的研究[4]。
体外实验中，GMX1778（30nM-1µM；24小时）显著降低了HT1080细胞内的NAD⁺水平，并诱导了细胞毒性[5]。GMX1778（5nM；48小时）显著增加了NAPRT1阴性癌细胞（如U251和MDA-MB-231BR细胞）内的活性氧（ROS）水平，并导致细胞凋亡[6]。
体内实验中，GMX1778（100mg/kg/周；给药3周；口服灌胃）在神经内分泌肿瘤（NET）异种移植小鼠模型中显著增强了177Lu-DOTATATE治疗的抗肿瘤效果，延长了肿瘤进展的中位时间，并减少了肿瘤体积[7]。