6GE0

Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2

6GE0 の概要

• エントリーDOI: 10.2210/pdb6ge0/pdb
• 分子名称: Mitogen-activated protein kinase 1, SULFATE ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: erk2 kinase inhibitor, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43590.59

構造登録者

O'Reilly, M. (登録日: 2018-04-25, 公開日: 2018-05-30, 最終更新日: 2024-10-16)

主引用文献

Heightman, T.D.,Berdini, V.,Braithwaite, H.,Buck, I.M.,Cassidy, M.,Castro, J.,Courtin, A.,Day, J.E.H.,East, C.,Fazal, L.,Graham, B.,Griffiths-Jones, C.M.,Lyons, J.F.,Martins, V.,Muench, S.,Munck, J.M.,Norton, D.,O'Reilly, M.,Palmer, N.,Pathuri, P.,Reader, M.,Rees, D.C.,Rich, S.J.,Richardson, C.,Saini, H.,Thompson, N.T.,Wallis, N.G.,Walton, H.,Wilsher, N.E.,Woolford, A.J.,Cooke, M.,Cousin, D.,Onions, S.,Shannon, J.,Watts, J.,Murray, C.W.
Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.
J. Med. Chem., 61:4978-4992, 2018

PubMed Abstract: Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.

PubMed: 29775310
DOI: 10.1021/acs.jmedchem.8b00421

実験手法

X-RAY DIFFRACTION (1.82 Å)