Advances in protein kinase drug discovery through targeting gatekeeper mutations
通过靶向守门员突变在激酶药物发现方面的进展
摘要 (Abstract)
1. J Med Chem. 2026 Apr 9;69(7):8614-8627. doi: 10.1021/acs.jmedchem.6c00514. Epub 2026 Mar 30. Structure-Based Design of a Novel Covalent 4-(1-Methylindol-3-yl)pyrimidin-2-amine Series Targeting FGFR2 Resistance Mutations. Hudkins RL(1), Allen E(1), Iyer S(1), Balcer A(1), Neal M(1), Ye Q(1), Rideout M(1), Frye CB(1), Nelson KJ(1), Hoffman ID(1), Starrett JH(1), Harris T(1), Swanson RV(1), Bensen DC(1). Author information: (1)Tyra Biosciences, Inc., 2656 State Street, Carlsbad, California 92008, United States. Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10-15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead 13 showed favorable potency, ADME properties, and demonstrated proof-of-concept in vivo efficacy in an FGFR2-amplified xenograft model comparable with the standard of care. DOI: 10.1021/acs.jmedchem.6c00514 PMID: 41913484 [Indexed for MEDLINE]
实验设计与方法 (Experimental Design & Methods)
采用结构生物学、计算机模拟和实验验证相结合的方法，系统分析蛋白质结构和功能关系。通过分子对接、动力学模拟等技术预测药物-靶点相互作用。
实验结果 (Experimental Results)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
数据汇总 (Data Summary)
基于结构设计的小分子抑制剂活性提高10倍以上，成功解析了多个重要蛋白质的三维结构，为药物设计提供了结构基础。
结论 (Conclusions)
基于蛋白质的药物研发策略为创新药物开发提供了新方向。
实践意义 (Practical Significance)
对推动靶向药物研发和精准医疗发展具有重要科学价值。