Lucas Stephanie, Soave Claire, Nabil Ghazal, Ahmed Zainab Sabry Othman, Chen Guohua, El-Banna Hossny Awad, Dou Q Ping, Wang Jian
Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201. United States.
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201. United States.
Recent Pat Anticancer Drug Discov. 2017;12(3):190-207. doi: 10.2174/1574892812666170619125503.
Alteration of cellular metabolism is a hallmark of cancer, which underlies exciting opportunities to develop effective, anti-cancer therapeutics through inhibition of cancer metabolism. Nicotinamide Adenine Dinucleotide (NAD+), an essential coenzyme of energy metabolism and a signaling molecule linking cellular energy status to a spectrum of molecular regulation, has been shown to be in high demand in a variety of cancer cells. Depletion of NAD+ by inhibition of its key biosynthetic enzymes has become an attractive strategy to target cancer.
The main objective of this article is to review the recent patents which develop and implicate the chemical inhibitors of the key NAD+ biosynthetic enzymes for cancer treatment. We first discuss the biological principles of NAD+ metabolism in normal and malignant cells, with a focus on the feasibility of selectively targeting cancer cells by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) and indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), the rate-limiting salvage and de novo NAD+ biosynthetic enzymes, respectively. We then analyze a series of recent patents on development and optimization of chemical scaffolds for inhibiting NAMPT or IDO/TDO enzymes as potential anticancer drugs. Conclusion and Results: We have reviewed 16 relevant patents published since 2015, and summarized the chemical properties, mechanisms of action and proposed applications of the patented compounds. Without a better understanding of the properties of these compounds, their utility for further optimization and clinical use is unknown. For the compounds that have been tested using cell and mouse models of cancer, results look promising and clinical trials are currently ongoing to see if these results translate to improved cancer treatments.
细胞代谢改变是癌症的一个标志，这为通过抑制癌症代谢开发有效抗癌疗法带来了令人兴奋的机遇。烟酰胺腺嘌呤二核苷酸（NAD+）是能量代谢的必需辅酶，也是将细胞能量状态与一系列分子调节联系起来的信号分子，已被证明在多种癌细胞中需求量很大。通过抑制其关键生物合成酶来消耗NAD+已成为一种有吸引力的癌症靶向策略。
本文的主要目的是综述最近开发并涉及用于癌症治疗的关键NAD+生物合成酶化学抑制剂的专利。我们首先讨论正常细胞和恶性细胞中NAD+代谢的生物学原理，重点关注通过药理学抑制烟酰胺磷酸核糖转移酶（NAMPT）和吲哚胺/色氨酸2,3-双加氧酶（IDO/TDO）来选择性靶向癌细胞的可行性，这两种酶分别是补救途径和从头合成途径中NAD+生物合成的限速酶。然后我们分析了一系列关于开发和优化用于抑制NAMPT或IDO/TDO酶作为潜在抗癌药物的化学支架的近期专利。结论与结果：我们综述了自2015年以来发表的16项相关专利，并总结了专利化合物的化学性质、作用机制和拟应用。如果不能更好地了解这些化合物的性质，它们在进一步优化和临床应用中的效用将是未知的。对于已在癌症细胞和小鼠模型中进行测试的化合物，结果看起来很有希望，目前正在进行临床试验，以确定这些结果是否能转化为改善癌症治疗效果。
