人类二氢烟酸脱氢酶 (hDHODH) 抑制剂作为抗癌剂及其他治疗应用的专利回顾(1999-2022 年)。

IF 2.5 4区 医学 Q3 ONCOLOGY
Pinky Gehlot, Vivek K Vyas
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引用次数: 0

摘要

癌细胞等高增殖细胞需要大量嘧啶核苷酸来增殖,而嘧啶核苷酸是通过从头嘧啶生物合成实现的。人类二氢烟酸脱氢酶(hDHODH)在嘧啶从头生物合成的限速步骤中起着至关重要的作用。作为公认的治疗靶点,hDHODH 在癌症和其他疾病中发挥着重要作用。在过去的二十年里,作为 hDHODH 酶抑制剂的小分子化合物作为抗癌药物及其在类风湿性关节炎(RA)和多发性硬化症(MS)中的作用引起了广泛关注。在本专利综述中,我们汇编了 1999 年至 2022 年间公布的 hDHODH 抑制剂专利,并讨论了作为抗癌剂的 hDHODH 抑制剂的发展情况。小分子 hDHODH 抑制剂在治疗癌症等各种疾病方面的治疗潜力已得到广泛认可。人类 DHODH 抑制剂可迅速导致细胞内单磷酸尿苷(UMP)耗竭,从而产生嘧啶碱饥饿。正常细胞可以更好地忍受短暂的饥饿,而不会受到传统细胞毒性药物的副作用影响,并能在抑制新生途径后利用替代性挽救途径恢复核酸合成和其他细胞功能。高增殖细胞(如癌细胞)无法忍受饥饿,因为它们需要大量核苷酸来进行细胞分化,而这需要从头嘧啶生物合成来实现。此外,与其他抗癌剂的细胞毒性剂量相比,hDHODH 抑制剂只需较低剂量就能产生所需的活性。因此,抑制嘧啶的新生物合成将为新型靶向抗癌药的开发开辟新的前景,而目前正在进行的临床前和临床实验也证明了这一点。我们的工作汇集了有关 hDHODH 在癌症中作用的全面专利综述,以及与 hDHODH 抑制剂及其抗癌和其他治疗潜力相关的各种专利。这份有关 DHODH 抑制剂专利的汇编将指导研究人员寻找最有希望的针对 hDHODH 酶的抗癌药物发现策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Patent Review of Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors as Anticancer Agents and their Other Therapeutic Applications (1999-2022).

Highly proliferating cells, such as cancer cells, are in high demand of pyrimidine nucleotides for their proliferation, accomplished by de novo pyrimidine biosynthesis. The human dihydroorotate dehydrogenase (hDHODH) enzyme plays a vital role in the rate-limiting step of de novo pyrimidine biosynthesis. As a recognised therapeutic target, hDHODH plays a significant role in cancer and other illness. In the past two decades, small molecules as inhibitors hDHODH enzyme have drawn much attention as anticancer agents, and their role in rheumatoid arthritis (RA), and multiple sclerosis (MS). In this patent review, we have compiled patented hDHODH inhibitors published between 1999 and 2022 and discussed the development of hDHODH inhibitors as anticancer agents. Therapeutic potential of small molecules as hDHODH inhibitors for the treatment of various diseases, such as cancer, is very well recognised. Human DHODH inhibitors can rapidly cause intracellular uridine monophosphate (UMP) depletion to produce starvation of pyrimidine bases. Normal cells can better endure a brief period of starvation without the side effects of conventional cytotoxic medication and resume synthesis of nucleic acid and other cellular functions after inhibition of de novo pathway using an alternative salvage pathway. Highly proliferative cells such as cancer cells do not endure starvation because they are in high demand of nucleotides for cell differentiation, which is fulfilled by de novo pyrimidine biosynthesis. In addition, hDHODH inhibitors produce their desired activity at lower doses rather than a cytotoxic dose of other anticancer agents. Thus, inhibition of de novo pyrimidine biosynthesis will create new prospects for the development of novel targeted anticancer agents, which ongoing preclinical and clinical experiments define. Our work brings together a comprehensive patent review of the role of hDHODH in cancer, as well as various patents related to the hDHODH inhibitors and their anticancer and other therapeutic potential. This compiled work on patented DHODH inhibitors will guide researchers in pursuing the most promising drug discovery strategies against the hDHODH enzyme as anticancer agents.

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来源期刊
CiteScore
4.50
自引率
7.10%
发文量
55
审稿时长
3 months
期刊介绍: Aims & Scope Recent Patents on Anti-Cancer Drug Discovery publishes review and research articles that reflect or deal with studies in relation to a patent, application of reported patents in a study, discussion of comparison of results regarding application of a given patent, etc., and also guest edited thematic issues on recent patents in the field of anti-cancer drug discovery e.g. on novel bioactive compounds, analogs, targets & predictive biomarkers & drug efficacy biomarkers. The journal also publishes book reviews of eBooks and books on anti-cancer drug discovery. A selection of important and recent patents on anti-cancer drug discovery is also included in the journal. The journal is essential reading for all researchers involved in anti-cancer drug design and discovery. The journal also covers recent research (where patents have been registered) in fast emerging therapeutic areas/targets & therapeutic agents related to anti-cancer drug discovery.
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