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The irreversible covalent fibroblast growth factor receptor inhibitor PRN1371 exhibits sustained inhibition of FGFR after drug clearance
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2017-10-04 , DOI: 10.1158/1535-7163.mct-17-0309
Eleni Venetsanakos , Ken A. Brameld , Vernon T. Phan , Erik Verner , Timothy D. Owens , Yan Xing , Danny Tam , Jacob LaStant , Kwan Leung , Dane E. Karr , Ronald J. Hill , Mary E. Gerritsen , David M. Goldstein , Jens Oliver Funk , J. Michael Bradshaw

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668–76. ©2017 AACR.

中文翻译:

不可逆共价成纤维细胞生长因子受体抑制剂 PRN1371 在药物清除后表现出对 FGFR 的持续抑制

已知越来越多的癌症在成纤维细胞生长因子受体 (FGFR) 激酶家族中存在突变、易位或扩增。迄今为止,在临床试验中评估的 FGFR 抑制剂已显示出治疗这些癌症的前景。在这里,我们描述了 PRN1371,一种不可逆的 FGFR1-4 共价抑制剂,靶向激酶活性位点内的半胱氨酸。PRN1371 在许多生化和细胞分析中表现出强大的 FGFR 效力和出色的全激酶组选择性,包​​括在表现出 FGFR 改变的各种癌细胞系中。此外,PRN1371 在体内维持 FGFR 抑制,不仅在循环药物水平高时,而且在药物从循环中清除后,表明在临床中持续抑制 FGFR 的可能性,而无需持续药物暴露。在多个肿瘤异种移植物和患者来源的肿瘤异种移植物模型中也获得了持久的肿瘤消退,并且即使使用提供药物假期的间歇给药策略也能持续。PRN1371 目前正在进行临床研究,用于治疗实体瘤患者。摩尔癌症治疗; 16(12); 2668-76。©2017 AACR。
更新日期:2017-10-04
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