Abstract：
Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.
摘要：
环肽由于其口服吸收的潜力和易于接近艰难的细胞内靶标而作为治疗剂受到关注。LUNA18，一种临床KRAS抑制剂，通过使用符合我们的药物相似性标准的mRNA展示文库，从最初的命中开始转化-没有支架跳跃。在使用mRNA展示文库的药物发现中，命中化合物总是具有与mRNA标签连接的位点。这里,我们描述了我们使用X射线结构对结构-活性关系（SAR）的检查，用于在与mRNA标签连接的位点附近进行化学优化，相当于C端。C-末端附近的结构修饰显示对侧链的相对宽范围的耐受性。此外，我们表明，单原子修饰足以改变药代动力学（PK）谱。由于在活性方面有四个允许侧链修饰的位置，可以通过结构优化侧链来灵活地调整药代动力学特征。此处证明的侧链转化发现通常可适用于从mRNA展示文库获得的命中。
