Laux Julian, Forster Michael, Riexinger Laura, Schwamborn Anna, Guezguez Jamil, Pokoj Christina, Kudolo Mark, Berger Lena M, Knapp Stefan, Schollmeyer Dieter, Guse Jan, Burnet Michael, Laufer Stefan A
Synovo GmbH, Paul-Ehrlich-Straße 15, 72076 Tübingen, Germany.
Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, DE Germany.
ACS Pharmacol Transl Sci. 2022 Jul 14;5(8):573-602. doi: 10.1021/acsptsci.2c00054. eCollection 2022 Aug 12.
Modulation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is a promising method of treating autoimmune diseases, and the profound potency of clinical compounds makes this mode of action particularly attractive. Other questions that remain unanswered also include: What is the ideal selectivity between JAK1 and JAK3? Which cells are most relevant to JAK blockade? And what is the ideal tissue distribution pattern for addressing specific autoimmune conditions? We hypothesized that JAK3 selectivity is most relevant to low-dose clinical effects and interleukin-10 (IL-10) stimulation in particular, that immune cells are the most important compartment, and that distribution to inflamed tissue is the most important pharmacokinetic characteristic for disease modification. To test these hypotheses, we prepared modified derivatives of JAK3 specific inhibitors that target C909 near the ATP binding site based on FM-381, first reported in 2016; a compound class that was hitherto limited in uptake and exposure . These limits appear to be due to metabolic instability of side groups binding in the selectivity pocket. We identified derivatives with improved stability and tissue exposure. Conjugation to macrolide scaffolds with medium chain linkers was sufficient to stabilize the compounds and improve transport to organs while maintaining JAK3 affinity. These conjugates are inflammation targeted JAK3 inhibitors with long tissue half-lives and high exposure to activated immune cells.
调节Janus激酶/信号转导子和转录激活子（JAK/STAT）信号通路是一种很有前景的治疗自身免疫性疾病的方法，临床化合物的强大效力使这种作用模式格外具有吸引力。其他尚未得到解答的问题还包括：JAK1和JAK3之间的理想选择性是多少？哪些细胞与JAK阻断最为相关？以及针对特定自身免疫性疾病的理想组织分布模式是怎样的？我们推测，JAK3选择性与低剂量临床效果尤其是白细胞介素-10（IL-10）刺激最为相关，免疫细胞是最重要的细胞区室，并且分布到炎症组织是疾病改善的最重要药代动力学特征。为了验证这些假设，我们基于2016年首次报道的FM-381制备了靶向ATP结合位点附近C909的JAK3特异性抑制剂的修饰衍生物；这一类化合物在摄取和暴露方面迄今受到限制。这些限制似乎是由于结合在选择性口袋中的侧链代谢不稳定所致。我们鉴定出了稳定性和组织暴露性得到改善的衍生物。与带有中链连接子的大环内酯支架共轭足以稳定化合物并改善向器官的转运，同时保持JAK3亲和力。这些共轭物是靶向炎症的JAK3抑制剂，具有较长的组织半衰期且在活化免疫细胞中有高暴露。
