Abstract：
BACKGROUND: c-Jun N-terminal kinases (JNKs) are involved in the emergence and progression of diverse pathologies such as neurodegenerative, cardiovascular and metabolic disorders as well as inflammation and cancer. In recent years, several highly selective pan-JNK inhibitors have been characterized and three chemical entities targeting JNKs have been investigated in clinical trials.
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.
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.
摘要：
背景：c-JunN末端激酶（JNKs）参与了各种病理的出现和进展，例如神经退行性疾病，心血管和代谢紊乱以及炎症和癌症。近年来,已经表征了几种高选择性泛JNK抑制剂,并在临床试验中研究了三种靶向JNK的化学实体.
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。
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。
