METHODS: This review summarizes patents claiming inhibitors of all JNK isoforms published between 2010 and 2014. Although primarily focusing on the patent literature, relevant peer-reviewed publications related to the covered patents have also been included. Moreover, key patents claiming novel applications of previously published chemical entities are reviewed. The article highlights a total of 28 patents from nine pharmaceutical companies and academic research groups.
CONCLUSIONS: Although some selective pan-JNK inhibitors with reasonable in vivo profiles are now available, little is known about the isoform selectivity required for each particular indication and the development of isoform-selective JNK inhibitors still represents a challenge in JNK drug discovery. Moreover, isoform-selective tool compounds are a prerequisite to a comprehensive understanding of the biology of each JNK isoform. Potential approaches towards such compounds include the design of type-II and type-I(1)/2 binders, which are absent in the current JNK inhibitor portfolios, as well as the design of novel allosteric inhibitors. Furthermore, covalent inhibition, which already led to the first high-quality probe for JNKs, might be further exploited for gaining selectivity and in vivo efficacy. With regard to a potential therapeutic application, the recently proposed concept of covalent reversible inhibitors is expected to be attractive.
方法:本综述总结了2010年至2014年间发表的所有JNK亚型抑制剂的专利。虽然主要关注专利文献,还包括与所涵盖专利有关的相关同行评审出版物。此外,审查了声称以前发表的化学实体的新应用的关键专利。本文重点介绍了来自9家制药公司和学术研究小组的28项专利。
结论:尽管现在有一些具有合理体内谱的选择性泛JNK抑制剂,对每种特定适应症所需的同工型选择性知之甚少,开发同工型选择性JNK抑制剂仍然是JNK药物发现的挑战.此外,同工型选择性工具化合物是全面了解每种JNK同工型生物学的先决条件。针对此类化合物的潜在方法包括II型和I型(1)/2粘合剂的设计,这在目前的JNK抑制剂投资组合中是不存在的,以及新型变构抑制剂的设计。此外,共价抑制,这已经导致了JNK的第一个高质量探针,可能被进一步开发用于获得选择性和体内功效。关于潜在的治疗应用,最近提出的共价可逆抑制剂的概念预计是有吸引力的。