PO.ET02.07 · 实验与分子治疗
比较性生化激酶活性分析确定 lirafugratinib 为高选择性 FGFR2 抑制剂
Comparative biochemical kinase activity analysis identifies lirafugratinib as a highly selective FGFR2 inhibitor
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：成纤维细胞生长因子受体（FGFR）的基因组改变发生于多种肿瘤类型，而泛 FGFR 抑制剂是 FGFR 融合阳性胆管癌（CCA）的标准治疗。近期的研究致力于设计更具选择性和共价的抑制剂，以提高疗效、安全性和耐受性。Lirafugratinib 是一种高选择性、不可逆的 FGFR2 抑制剂，旨在靶向致癌性 FGFR2 改变，从而在提高疗效结局的同时，不因抑制其他 FGFR 亚型（例如分别与 FGFR1 和 FGFR4 相关的高磷血症和腹泻）而加重毒性。
方法：为了解和比较 lirafugratinib 激酶抑制的相对选择性，我们针对四种泛 FGFR 抑制剂进行了头对头生化分析。使用 KINOMEscan 分析服务 scanMAX 和 TREEspot™ 相互作用图谱来评估和可视化激酶抑制情况：在 500 nM 浓度下，对 lirafugratinib 和其他四种泛 FGFR 抑制剂（futibatinib、pemigatinib、erdafitinib 和 AZD4547）测试了包含 468 种人类靶激酶和疾病相关激酶突变变体的组合。基于已确立并发表的激酶组图谱相关方法学研究，选择了 90% 和 75% 的抑制阈值。
结果：在 468 种激酶和疾病相关激酶突变体中，500 nM 的 lirafugratinib 仅抑制了两种激酶超过 90%（FGFR2 [94.1%] 和 MEK5 [92.4%]）。其余激酶，包括 FGFR1、FGFR3 和 FGFR4，除 MKNK2（89% 抑制）外，抑制率均 <75%。相比之下，futibatinib 对 FGFR1、FGFR2、FGFR3 和 FGFR4 的抑制均超过 90%，同时除 MKK7（83% 抑制）外，对其他激酶的抑制极小（<75%）。同样，pemigatinib、erdafitinib 和 AZD4547 分别以超过 90% 的抑制率抑制了多种激酶（包括所有 FGFR）——分别为 11、37 和 37 个激酶靶点。总体而言，与所测试的 FGFR 抑制剂相比，lirafugratinib 表现出最高的选择性，可抑制 FGFR2 而不显著抑制 FGFR1、FGFR3 和 FGFR4。
结论：对 lirafugratinib 和其他四种 FGFR 抑制剂的头对头激酶组分析显示，lirafugratinib 以高选择性抑制 FGFR2，提示与临床实践中使用的泛 FGFR 抑制剂相比，其脱靶和脱亚型相关毒性极小。
查看英文原文 English abstract
Background: Genomic alterations in fibroblast growth factor receptor (FGFR) occur across tumor types and pan-FGFR inhibitors are standard-of-care in FGFR fusion positive cholangiocarcinoma (CCA). Recent efforts focused on designing more selective and covalent inhibitors to improve efficacy, safety, and tolerability. Lirafugratinib, a highly selective and irreversible FGFR2 inhibitor, was designed to target oncogenic FGFR2 alterations to enhance efficacy outcomes without worsening toxicities due to inhibitions of other FGFR iso-forms (e.g., hyperphosphatemia and diarrhea related to FGFR1 and FGFR4, respectively).
Methods: To understand and compare the relative selectivity of lirafugratinib kinase inhibition, we performed a head-to-head biochemical analysis against four pan-FGFR inhibitors. A KINOMEscan Profiling Service scanMAX and TREEspot™ interaction maps were used for evaluation and visualization of inhibition of kinases: a panel of 468 human target kinases and disease-relevant kinase mutant variants were tested at a concentration of 500 nM for lirafugratinib and four other pan-FGFR inhibitors (futibatinib, pemigatinib, erdafitinib, and AZD4547). The 90% and 75% inhibition thresholds were selected based on established and published research for methodologies related to kinome mapping.
Results: Among the 468 kinases and disease-relevant kinase mutants, lirafugratinib at 500 nM inhibited >90% of only two kinases (FGFR2 [94.1%] and MEK5 [92.4%]). The rest of kinases, including FGFR1, FGFR3 and FGFR4, were inhibited <75% except MKNK2 (89% inhibition). In contrast, futibatinib inhibited FGFR1, FRFR2, FRFR3, and FGFR4 by more than 90%, while showing minimal (<75%) inhibition of other kinases except MKK7 (83% inhibition). Similarly, pemigatinib, erdafitinib, and AZD4547 inhibited multiple kinases (including all FGFRs) - 11, 37, and 37 kinase targets, by more than 90%. Overall, lirafugratinib demonstrated the highest selectivity to inhibit FGFR2 without substantial inhibition of FGFR1, FGFR3 and FGFR4, compared to the FGFR inhibitors tested.
Conclusions: The head-to-head kinome analysis of lirafugratinib and four other FGFR inhibitors revealed that lirafugratinib inhibited FGFR2 with high selectivity, suggesting minimal off-target and off-isoform-related toxicities compared to pan-FGFR inhibitors used in clinical practice.
利益披露 Disclosure
A. M. Schram,
Blueprint Bio Other, Consulting fees.
Flagship Pioneering Other, Consulting fees.
Redona Therapeutics Other, Consulting fees.
Schrodinger Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Relay Therapeutics Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Merus Other, Participation on a Data Safety Monitoring Board or Advisory Board.
PMV Pharmaceuticals Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Mersana Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Day One Biopharmaceuticals Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Guardant Other, Participation on a Data Safety Monitoring Board or Advisory Board.
Boehringer Ingelheim Other, Participation on a Data Safety Monitoring Board or Advisory Board.
G. Lee,
Elevar Therapeutics Employment.
T. Wei,
Elevar Therapeutics Employment.
S. Jang,
Elevar Therapeutics Employment.
K. Ryan,
Elevar Therapeutics Employment.