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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38 alpha and BRD4
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Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38 alpha and BRD4

机译：用P38α和BRD4的选择性鉴定新的口服生物可利用的ERK5抑制剂

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摘要

Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4 position with an aroyl group being found to exhibit 1050 values in the micromolar range, but having no selectivity against p38 alpha MAP kinase. Truncation of the N-substituent marginally enhanced potency (similar to 3-fold) against ERK5, but importantly attenuated inhibition of p38 alpha. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoy1)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 mu M for ERK5; IC50 > 120 mu M for p38 alpha). The crystal structure (PDB 5071) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：细胞外调节激酶5（ERK5）信号传导已经牵涉于驱动许多细胞表型包括内皮细胞的血管生成和肿瘤细胞运动性的。新颖ERK5抑制剂使用高通量筛选，用一系列吡咯-2-羧酰胺在与芳酰基作为4位被取代的鉴定发现在微摩尔范围内显示出1050倍的值，但具有抗p38阿尔法MAP激酶没有选择性。 N-取代基的截短略有增强的效力（类似于3倍）对ERK5，但重要的减毒的p38的α的抑制。上导致了选择性抑制剂4-（2-溴-6- fluorobenzoy1）-N-（吡啶-3-基）-1H-吡咯-2-甲酰胺（IC50 0.82微米为ERK5的芳酰基的取代基的系统性变化IC 50> 120微米为p38的阿尔法）。此化合物在复合体与ERK5的晶体结构（PDB 5071）解决了。该化合物是口服可生物利用，抑制bFGF的驱动基质胶塞血管生成和肿瘤异种移植物生长。选择性ERK5抑制剂本文描述提供了用于进一步开发成工具化合物为寻求检查的ERK5在癌症和其他疾病的信令中的作用更广泛的研究的引线。 （c）2019年Elsevier Masson SAS。版权所有。

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    Myers Stephanie M.; Miller Duncan C.; Molyneux Lauren; Arasta Mercedes; Bawn Ruth H.; Blackburn Timothy J.; Cook Simon J.; Edwards Noel; Endicott Jane A.; Golding Bernard T.; Griffin Roger J.; Hammonds Tim; Hardcastle Ian R.; Harnor Suzannah J.; Heptinstall Amy B.; Lochhead Pamela A.; Martin Mathew P.; Martin Nick C.; Newell David R.; Owen Paul J.; Pang Leon C.; Reuillo Tristan; Rigoreau Laurent J. M.; Thomas Huw D.; Tucker Julie A.; Wang Lan-Zhen; Wong Ai-Ching; Noble Martin E. M.; Wedge Stephen R.; Cano Celine;

  • 作者单位

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Babraham Inst Signalling Lab Babraham Res Campus Cambridge CB22 3AT England;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    London Biosci Innovat Ctr Canc Res UK Therapeut Discovery Labs 2 Royal Coll St London NW1 0NH;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Babraham Inst Signalling Lab Babraham Res Campus Cambridge CB22 3AT England;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    London Biosci Innovat Ctr Canc Res UK Therapeut Discovery Labs 2 Royal Coll St London NW1 0NH;

    London Biosci Innovat Ctr Canc Res UK Therapeut Discovery Labs 2 Royal Coll St London NW1 0NH;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

    Canc Res UK Therapeut Discovery Labs Jonas Webb Bldg Babraham Campus Babraham CB22 3AT Cambs;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    London Biosci Innovat Ctr Canc Res UK Therapeut Discovery Labs 2 Royal Coll St London NW1 0NH;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Med Sch Northern Inst Canc Res Newcastle Drug Discovery Paul OGorman Bldg Framlington Pl;

    Newcastle Univ Sch Chem Northern Inst Canc Res Newcastle Drug Discovery Bedson Bldg Newcastle;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    ERK5; Extracellular regulated kinase 5; BMK1; Kinase; Bioavailable; Pyrrole carboxamide;

    机译：ERK5;细胞外调节激酶5;BMK1;激酶;生物可利用;吡咯羧酰胺;

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