Medicinal Chemistry, Biogen, Inc, Cambridge, MA, USA.
Expert Opin Ther Pat. 2022 Apr;32(4):365-379. doi: 10.1080/13543776.2022.2026927. Epub 2022 Jan 31.
Tyrosine kinase 2 (TYK2) is a member of the JAK family class of kinases that is responsible for mediating the immune response to IL-12, IL-23, and IFNα. The therapeutic value of targeting this pathway in autoimmune diseases is supported by human genetics and multiple companies are developing small-molecule inhibitors as potential new treatments.
This article seeks to give a comprehensive review of the applications related to selective small-molecule TYK2 inhibition since the last publication in this journal in 2019. Recent regulatory activity, emerging clinical data, and new companies entering the clinic with selective TYK2 inhibitors will also be discussed.
Over the past 3 years there has been an increase in the number of companies and patent applications claiming selective TYK2 inhibitors. Deucravacitinib, an allosteric TYK2 inhibitor discovered by BMS, is the most advanced molecule in clinical development and in 2021, it received positive phase 3 data for the treatment of plaque psoriasis. . This development has spurred a renewed interest in targeting TYK2 with selective inhibitors and several new molecules have recently entered phase 1 trials. The research interest in this area is likely to further increase as additional clinical data with deucravacitinib and other TYK2 inhibitors continue to emerge.
酪氨酸激酶 2(TYK2)是 JAK 家族激酶类的成员,负责介导对白细胞介素 12(IL-12)、白细胞介素 23(IL-23)和干扰素-α(IFNα)的免疫反应。靶向该通路治疗自身免疫性疾病的治疗价值得到了人类遗传学的支持,多家公司正在开发小分子抑制剂作为潜在的新疗法。
本文旨在对自 2019 年本刊上次发表以来与选择性小分子 TYK2 抑制相关的应用进行全面综述。最近的监管活动、新兴的临床数据以及新进入临床阶段的具有选择性 TYK2 抑制剂的公司也将进行讨论。
在过去的 3 年中,声称具有选择性 TYK2 抑制剂的公司和专利申请数量有所增加。BMS 发现的别构 TYK2 抑制剂德瓦鲁单抗是临床开发中最先进的分子,2021 年,它在治疗斑块状银屑病方面获得了积极的 3 期数据。这一发展激发了人们对使用选择性抑制剂靶向 TYK2 的新兴趣,最近几个新分子已进入 1 期试验。随着更多关于德瓦鲁单抗和其他 TYK2 抑制剂的临床数据不断涌现,该领域的研究兴趣可能会进一步增加。