Lin Qianmeng, Chen Xiaojuan, Qu Lingzhi, Guo Ming, Wei Hudie, Dai Shuyan, Jiang Longying, Chen Yongheng
Department of Oncology, Department of Pathology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Commun Chem. 2022 Aug 22;5(1):100. doi: 10.1038/s42004-022-00718-z.
Fibroblast growth factor receptor (FGFR) dysregulation is involved in a variety of tumorigenesis and development. Cholangiocarcinoma is closely related with FGFR aberrations, and pemigatinib is the first drug approved to target FGFR for the treatment of cholangiocarcinoma. Herein, we undertake biochemical and structural analysis on pemigatinib against FGFRs as well as gatekeeper mutations. The results show that pemigatinib is a potent and selective FGFR1-3 inhibitor. The extensive network of hydrogen bonds and van der Waals contacts found in the FGFR1-pemigatinib binding mode accounts for the high potency. Pemigatinib also has excellent potency against the Val-to-Ile gatekeeper mutation but less potency against the Val-to-Met/Phe gatekeeper mutation in FGFR. Taken together, the inhibitory and structural profiles exemplified by pemigatinib may help to thwart Val-to-Ile gatekeeper mutation-based resistance at earlier administration and to advance the further design and improvement for inhibitors toward FGFRs with gatekeeper mutations.
成纤维细胞生长因子受体（FGFR）失调参与多种肿瘤的发生和发展。胆管癌与FGFR畸变密切相关，培米替尼是首个获批用于靶向FGFR治疗胆管癌的药物。在此，我们对培米替尼针对FGFR以及守门人突变进行了生化和结构分析。结果表明，培米替尼是一种强效且选择性的FGFR1-3抑制剂。在FGFR1-培米替尼结合模式中发现的广泛氢键和范德华接触网络解释了其高效性。培米替尼对FGFR中的缬氨酸到异亮氨酸守门人突变也具有优异的活性，但对缬氨酸到甲硫氨酸/苯丙氨酸守门人突变的活性较低。综上所述，培米替尼所体现的抑制和结构特征可能有助于在早期给药时对抗基于缬氨酸到异亮氨酸守门人突变的耐药性，并推动针对具有守门人突变的FGFR抑制剂的进一步设计和改进。
