Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor

Miller, DC; Reuillon, T; Molyneux, L; Blackburn, T; Cook, SJ; Edwards, N; Endicott, JA; Golding, BT; Griffin, RJ; Hardcastle, I; Harnor, SJ; Heptinstall, A; Lochhead, P; Martin, MP; Martin, NC; Newell, DR; Noble, RA; Phillips, N; Rigoreau, L; Thomas, H; Tucker, JA; Wang, LZ; Waring, MJ; Wong, AC; Wedge, SR; Noble, MEM; Cano, C

Abstract

The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has beenimplicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractiveapproach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, wedescribed the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor ofERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for targetvalidation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency andin vitropharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibitionand oral exposure.

Citation

Miller, D., Reuillon, T., Molyneux, L., Blackburn, T., Cook, S., Edwards, N., …Cano, C. (2022). Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor. Journal of Medicinal Chemistry, 65(9), 6513-6540. https://doi.org/10.1021/acs.jmedchem.1c01756

• Journal Article Type: Article
• Acceptance Date: Apr 11, 2022
• Publication Date: Apr 25, 2022
• Deposit Date: Sep 28, 2022
• Publicly Available Date: Sep 28, 2022
• Print ISSN: 0022-2623
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 65
• Issue: 9
• Pages: 6513-6540
• DOI: https://doi.org/10.1021/acs.jmedchem.1c01756
• Keywords: SELECTIVE INHIBITORS; RING; DERIVATIVES; GROWTH; SALTS