Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.
Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.
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DOI：
10.1021/acs.jmedchem.1c01756
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发表时间：
2022-05-12
影响因子：
7.3
通讯作者：
Cano, Celine
中科院分区：
文献类型：
--
作者：
Miller, Duncan C.;Reuillon, Tristan;Molyneux, Lauren;Blackburn, Timothy;Cook, Simon J.;Edwards, Noel;Endicott, Jane A.;Golding, Bernard T.;Griffin, Roger J.;Hardcastle, Ian;Harnor, Suzannah J.;Heptinstall, Amy;Lochhead, Pamela;Martin, Mathew P.;Martin, Nick C.;Myers, Stephanie;Newell, David R.;Noble, Richard A.;Phillips, Nicole;Rigoreau, Laurent;Thomas, Huw;Tucker, Julie A.;Wang, Lan-Zhen;Waring, Michael J.;Wong, Ai-Ching;Wedge, Stephen R.;Noble, Martin E. M.;Cano, Celine
非经典细胞外信号相关激酶5 （ERK5）有丝分裂原激活的蛋白激酶途径与细胞增殖、迁移、存活和血管生成的增加有关；因此，抑制ERK5可能是一种有吸引力的癌症治疗方法。然而，选择性ERK5抑制剂的开发一直具有挑战性。在此之前，我们描述了一种吡咯羧酰胺高通量筛选击中ERK5激酶活性的选择性亚微摩尔抑制剂的发展。提高ERK5的效价是鉴定ERK5抑制剂用于靶标验证研究的必要条件。在此，我们描述了该系列的优化，以鉴定含有碱性中心的ERK5纳米摩尔吡咯羧酰胺抑制剂，其口服生物利用度较差。平行优化效价和体外药代动力学参数，鉴定出一种具有ERK5抑制和口服暴露最佳平衡的非碱性吡唑类似物。
The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.
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影响因子：
9.7
作者：
Hoang VT;Yan TJ;Cavanaugh JE;Flaherty PT;Beckman BS;Burow ME
通讯作者：
Burow ME
影响因子：
8
作者：
McCracken, S. R. C.;Ramsay, A.;Leung, H. Y.
通讯作者：
Leung, H. Y.
DOI：
10.1107/s2059798316004502
发表时间：
2016-05
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Chen H;Tucker J;Wang X;Gavine PR;Phillips C;Augustin MA;Schreiner P;Steinbacher S;Preston M;Ogg D
通讯作者：
Ogg D
影响因子：
16.6
作者：
McFarland JM;Ho ZV;Kugener G;Dempster JM;Montgomery PG;Bryan JG;Krill-Burger JM;Green TM;Vazquez F;Boehm JS;Golub TR;Hahn WC;Root DE;Tsherniak A
通讯作者：
Tsherniak A
DOI：
10.1073/pnas.1609019113
发表时间：
2016-10-18
影响因子：
11.1
作者：
Lin, Emme C. K.;Amantea, Christopher M.;Rosenblum, Jonathan S.
通讯作者：
Rosenblum, Jonathan S.