一种用于创建共价FGFR抑制剂的结构导向方法。
A structure-guided approach to creating covalent FGFR inhibitors.
作者信息
Zhou Wenjun, Hur Wooyoung, McDermott Ultan, Dutt Amit, Xian Wa, Ficarro Scott B, Zhang Jianming, Sharma Sreenath V, Brugge Joan, Meyerson Matthew, Settleman Jeffrey, Gray Nathanael S
机构信息
Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Chem Biol. 2010 Mar 26;17(3):285-95. doi: 10.1016/j.chembiol.2010.02.007.
Abstract
The fibroblast growth factor receptor tyrosine kinases (FGFR1, 2, 3, and 4) represent promising therapeutic targets in a number of cancers. We have developed the first potent and selective irreversible inhibitor of FGFR1, 2, 3, and 4, which we named FIIN-1 that forms a covalent bond with cysteine 486 located in the P loop of the FGFR1 ATP binding site. We demonstrated that the inhibitor potently inhibits Tel-FGFR1-transformed Ba/F3 cells (EC(50) = 14 nM) as well as numerous FGFR-dependent cancer cell lines. A biotin-derivatized version of the inhibitor, FIIN-1-biotin, was shown to covalently label FGFR1 at Cys486. FIIN-1 is a useful probe of FGFR-dependent cellular phenomena and may provide a starting point of the development of therapeutically relevant irreversible inhibitors of wild-type and drug-resistant forms of FGFR kinases.
摘要
成纤维细胞生长因子受体酪氨酸激酶（FGFR1、2、3和4）是多种癌症中颇具前景的治疗靶点。我们研发出了首个强效且选择性的FGFR1、2、3和4不可逆抑制剂，命名为FIIN-1，它与位于FGFR1 ATP结合位点P环中的半胱氨酸486形成共价键。我们证明该抑制剂能有效抑制Tel-FGFR1转化的Ba/F3细胞（半数有效浓度[EC(50)] = 14 nM）以及众多FGFR依赖性癌细胞系。抑制剂的生物素衍生版本FIIN-1-生物素，被证明能在半胱氨酸486处共价标记FGFR1。FIIN-1是研究FGFR依赖性细胞现象的有用探针，可能为开发治疗相关的野生型和耐药型FGFR激酶不可逆抑制剂提供一个起点。
相似文献
1
A structure-guided approach to creating covalent FGFR inhibitors.一种用于创建共价FGFR抑制剂的结构导向方法。
Chem Biol. 2010 Mar 26;17(3):285-95. doi: 10.1016/j.chembiol.2010.02.007.
2
Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression.共激活受体酪氨酸激酶减轻了FGFR1蛋白表达低的FGFR1扩增肺癌中FGFR抑制剂的作用。
Oncogene. 2016 Jul 7;35(27):3587-97. doi: 10.1038/onc.2015.426. Epub 2015 Nov 9.
3
Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.能够克服对第一代FGFR激酶抑制剂耐药性的共价抑制剂的研发。
Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):E4869-77. doi: 10.1073/pnas.1403438111. Epub 2014 Oct 27.
4
Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors.发现强效不可逆泛成纤维细胞生长因子受体（FGFR）抑制剂。
J Med Chem. 2018 Oct 25;61(20):9085-9104. doi: 10.1021/acs.jmedchem.7b01843. Epub 2018 Mar 16.
5
Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors.富替替尼是一种新型不可逆 FGFR1-4 抑制剂，对 FGFR 失调肿瘤具有选择性抗肿瘤活性。
Cancer Res. 2020 Nov 15;80(22):4986-4997. doi: 10.1158/0008-5472.CAN-19-2568. Epub 2020 Sep 24.
6
Structure-activity relationship studies of Imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine derivatives to develop selective FGFR inhibitors as anticancer agents for FGF19-overexpressed hepatocellular carcinoma.咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶衍生物的构效关系研究，以开发选择性FGFR抑制剂作为FGF19过表达肝细胞癌的抗癌药物。
Eur J Med Chem. 2025 Jan 15;282:117047. doi: 10.1016/j.ejmech.2024.117047. Epub 2024 Nov 12.
7
Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.成纤维细胞生长因子受体的共价靶向作用可抑制转移性乳腺癌。
Mol Cancer Ther. 2016 Sep;15(9):2096-106. doi: 10.1158/1535-7163.MCT-16-0136. Epub 2016 Jul 1.
8
Integrative Multi-Omics Approaches Reveal Selectivity Profiles and Molecular Mechanisms of FIIN-2, a Covalent FGFR Inhibitor.整合多组学方法揭示共价FGFR抑制剂FIIN-2的选择性概况和分子机制。
Adv Sci (Weinh). 2025 Apr;12(14):e2412578. doi: 10.1002/advs.202412578. Epub 2025 Feb 20.
9
DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo.DW14383 是一种不可逆的泛 FGFR 抑制剂，能在体外和体内抑制 FGFR 依赖性肿瘤生长。
Acta Pharmacol Sin. 2021 Sep;42(9):1498-1506. doi: 10.1038/s41401-020-00567-3. Epub 2020 Dec 7.
10
[Pharmacological characteristics and clinical effectiveness of Futibatinib (Lytgobi Tablets), a covalently-binding, irreversible FGFR1-4 inhibitor].共价结合、不可逆的FGFR1-4抑制剂富替巴替尼（Lytgobi片）的药理特性及临床疗效
Nihon Yakurigaku Zasshi. 2024 Nov 1;159(6):423-432. doi: 10.1254/fpj.24045. Epub 2024 Oct 10.
引用本文的文献
1
Computational Design of Lysine Targeting Covalent Binders Using Rosetta.使用Rosetta进行赖氨酸靶向共价结合物的计算设计
J Chem Inf Model. 2025 May 29. doi: 10.1021/acs.jcim.5c00212.
2
Targeting Glioma Stem Cells: Therapeutic Opportunities and Challenges.靶向胶质瘤干细胞：治疗机遇与挑战
Cells. 2025 May 6;14(9):675. doi: 10.3390/cells14090675.
3
Targeting the cancer cells and cancer-associated fibroblasts with next-generation FGFR inhibitors in prostate cancer co-culture models.在前列腺癌共培养模型中，使用下一代 FGFR 抑制剂靶向癌细胞和癌相关成纤维细胞。
Cancer Med. 2024 Sep;13(18):e70240. doi: 10.1002/cam4.70240.
4
Advances in reversible covalent kinase inhibitors.可逆共价激酶抑制剂的研究进展。
Med Res Rev. 2025 Mar;45(2):629-653. doi: 10.1002/med.22084. Epub 2024 Sep 17.
5
Targeting FGFR for cancer therapy.针对成纤维细胞生长因子受体（FGFR）的癌症治疗策略。
J Hematol Oncol. 2024 Jun 3;17(1):39. doi: 10.1186/s13045-024-01558-1.
6
Developing a Kinase Chemogenomic Set: Facilitating Investigation into Kinase Biology by Linking Phenotypes to Targets.开发激酶化学基因组集：通过将表型与靶标联系起来，促进激酶生物学的研究。
Methods Mol Biol. 2023;2706:11-24. doi: 10.1007/978-1-0716-3397-7_2.
7
Discovery of Futibatinib: The First Covalent FGFR Kinase Inhibitor in Clinical Use.呋喹替尼的发现：首个临床应用的共价FGFR激酶抑制剂
ACS Med Chem Lett. 2023 Mar 10;14(4):396-404. doi: 10.1021/acsmedchemlett.3c00006. eCollection 2023 Apr 13.
8
Structural insights into the potency and selectivity of covalent pan-FGFR inhibitors.共价泛FGFR抑制剂效力和选择性的结构见解
Commun Chem. 2022 Jan 11;5(1):5. doi: 10.1038/s42004-021-00623-x.
9
Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling.成纤维细胞生长因子信号对肺泡细胞命运选择和 AT2 细胞的终身维持。
Nat Commun. 2022 Nov 21;13(1):7137. doi: 10.1038/s41467-022-34059-1.
10
Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review.FGFR的信号通路与小分子药物发现：全面综述
Front Chem. 2022 Apr 14;10:860985. doi: 10.3389/fchem.2022.860985. eCollection 2022.
本文引用的文献
1
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.新型选择性 EGFR 激酶抑制剂，针对 EGFR T790M。
Nature. 2009 Dec 24;462(7276):1070-4. doi: 10.1038/nature08622.
2
Targeting cancer with small molecule kinase inhibitors.用小分子激酶抑制剂靶向治疗癌症。
Nat Rev Cancer. 2009 Jan;9(1):28-39. doi: 10.1038/nrc2559.
3
Activation of tyrosine kinases by mutation of the gatekeeper threonine.通过守门苏氨酸突变激活酪氨酸激酶。
Nat Struct Mol Biol. 2008 Oct;15(10):1109-18. doi: 10.1038/nsmb.1486. Epub 2008 Sep 14.
4
Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase.临床阶段的表皮生长因子受体（EGFR）抑制剂可不可逆地使Bmx激酶烷基化。
Bioorg Med Chem Lett. 2008 Nov 15;18(22):5916-9. doi: 10.1016/j.bmcl.2008.07.062. Epub 2008 Jul 18.
5
Drug-sensitive FGFR2 mutations in endometrial carcinoma.子宫内膜癌中的药物敏感性成纤维细胞生长因子受体2（FGFR2）突变
Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8713-7. doi: 10.1073/pnas.0803379105. Epub 2008 Jun 13.
6
Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.FGFR2的等位基因特异性上调增加了患乳腺癌的易感性。
PLoS Biol. 2008 May 6;6(5):e108. doi: 10.1371/journal.pbio.0060108.
7
FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival.FGFR2扩增的胃癌细胞系生长和存活需要FGFR2和Erbb3信号传导。
Cancer Res. 2008 Apr 1;68(7):2340-8. doi: 10.1158/0008-5472.CAN-07-5229.
8
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.表皮生长因子受体（EGFR）激酶中的T790M突变通过增加对三磷酸腺苷（ATP）的亲和力导致耐药性。
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5. doi: 10.1073/pnas.0709662105. Epub 2008 Jan 28.
9
A quantitative analysis of kinase inhibitor selectivity.激酶抑制剂选择性的定量分析。
Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358.
10
Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.通过高通量肿瘤细胞系分析鉴定与基因型相关的对选择性激酶抑制剂的敏感性
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19936-41. doi: 10.1073/pnas.0707498104. Epub 2007 Dec 6.
Zotero 插件