Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein–Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases

Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein–protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.

白细胞介素17A（Interleukin 17A，IL-17A）属于白细胞介素类细胞因子，其表达失调与银屑病等自身免疫疾病密切相关，靶向IL-17A通路的单克隆抗体现已成为成熟且高效的临床治疗手段。本文详细阐述了将化合物23开发为口服小分子蛋白质相互作用调节剂（protein–protein interaction modulator，PPIm）临床开发候选化合物的完整研究工作。蛋白质晶体学技术解析了小分子配体与IL-17A二聚体之间的关键结合相互作用，为通过多参数优化筛选符合类药五规则（Rule of 5）、具备口服生物利用度的IL-17A靶向PPIm提供了核心结构依据。通过对早期配体进行结构叠合分析，研究人员得到了一系列含二苯甲基甘氨酸的化合物，并成功鉴定出二甲基吡唑作为关键取代基，可使所得PPIm具备口服生物利用度。随后对该分子结构中的氨基酸片段开展构效关系探索，最终发现二环丙基丙氨酸基团可赋予化合物强效且代谢稳定的特性，由此得到了本研究的临床开发候选化合物23。