靶向“不可成药”的致病蛋白：聚焦信号转导和转录激活因子 3（STAT3）
DRUGGING "UNDRUGGABLE" DISEASE-CAUSING PROTEINS: FOCUS ON SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 3.
机构信息
HOUSTON, TEXAS.
出版信息
Trans Am Clin Climatol Assoc. 2022;132:61-76.
Abstract
Signal transducer and activator of transcription (STAT) 3 has been assigned to the group of "undruggable" disease-causing proteins, despite its containing a Src-homology (SH) 2 domain, a potential Achilles' heel that has eluded successful targeting by academic and pharmaceutical groups over the past 30 years. Based on mutational and modeling studies, our group developed a unique virtual ligand screening strategy targeting the STAT3 SH2 domain that was coupled to robust biochemical and cellular assays and structure-based medicinal chemistry and led to the identification of TTI-101. TTI-101 represents one of the most advanced, direct, small-molecule inhibitors of an SH2 domain-containing, disease-causing protein in clinical development. TTI-101 is currently being evaluated in a Phase 1 study to determine safety and tolerability in addition to pharmacodynamic effects and efficacy in patients with advanced solid tumors.
摘要
信号转导子和转录激活子 (STAT) 3 被归为“不可成药”的致病蛋白组，尽管它含有Src 同源（SH）2 结构域，这是一个潜在的致命弱点，过去 30 年来，学术界和制药界一直未能成功靶向该弱点。基于突变和建模研究，我们的团队开发了一种针对 STAT3 SH2 结构域的独特虚拟配体筛选策略，该策略与强大的生化和细胞测定、基于结构的药物化学相结合，并导致了 TTI-101 的发现。TTI-101 是目前正在临床开发中针对包含 SH2 结构域的致病蛋白的最先进、直接的小分子抑制剂之一。TTI-101 目前正在进行 I 期研究，以确定其在晚期实体瘤患者中的安全性和耐受性、药效学作用以及疗效。
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