5NGU

Human Erk2 with an Erk1/2 inhibitor

Summary for 5NGU

• Entry DOI: 10.2210/pdb5ngu/pdb
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, 2-[2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]pyrimidin-4-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one, ... (4 entities in total)
• Functional Keywords: erk2, kinase, inhibitor, oncology, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, spindle : P28482
• Total number of polymer chains: 1
• Total formula weight: 44581.02

Authors

Debreczeni, J.E.,Ward, R.A.,Bethel, P.,Cook, C.,Davies, E.,Eckersley, K.,Fairley, G.,Feron, L.,Flemington, V.,Graham, M.A.,Greenwood, R.,Hopcroft, P.,Howard, T.D.,Hudson, J.,James, M.,Jones, C.D.,Jones, C.R.,Lamont, S.,Lewis, R.,Lindsay, N.,Roberts, K.,Simpson, I.,StGallay, S.,Swallow, S.,Tonge, M. (deposition date: 2017-03-20, release date: 2017-04-19, Last modification date: 2024-11-13)

Primary citation

Ward, R.A.,Bethel, P.,Cook, C.,Davies, E.,Debreczeni, J.E.,Fairley, G.,Feron, L.,Flemington, V.,Graham, M.A.,Greenwood, R.,Griffin, N.,Hanson, L.,Hopcroft, P.,Howard, T.D.,Hudson, J.,James, M.,Jones, C.D.,Jones, C.R.,Lamont, S.,Lewis, R.,Lindsay, N.,Roberts, K.,Simpson, I.,St-Gallay, S.,Swallow, S.,Tang, J.,Tonge, M.,Wang, Z.,Zhai, B.
Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.
J. Med. Chem., 60:3438-3450, 2017

PubMed Abstract: There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.

PubMed: 28376306
DOI: 10.1021/acs.jmedchem.7b00267

Experimental method

X-RAY DIFFRACTION (2.74 Å)