PDBsum entry 6g9h

Signaling protein

PDB id: 6g9h

Contents

Protein chain

344 a.a.

Ligands

SO4 ×4

ERW

Waters ×456

PDB id:

6g9h

Name:

Signaling protein

Title:

Fragment-based discovery of a highly potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of erk1/2

Structure:

Mitogen-activated protein kinase 1. Chain: a. Synonym: mapk 1,ert1,extracellular signal-regulated kinase 2,erk-2, map kinase isoform p42,p42-mapk,mitogen-activated protein kinase 2, mapk 2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk1, erk2, prkm1, prkm2. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693

Resolution:

1.73Å R-factor: 0.164 R-free: 0.213

Authors:

M.O'Reilly

Key ref:

T.D.Heightman et al. (2018). 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. PubMed id: 29775310 DOI: 10.1021/acs.jmedchem.8b00421

Date:

10-Apr-18 Release date: 30-May-18

Protein chain

P28482  (MK01_HUMAN) -  Mitogen-activated protein kinase 1 from Homo sapiens

Seq: 360 a.a.

Struc: 344 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.11.24 - mitogen-activated protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.8b00421

J Med Chem 61:4978-4992 (2018)

PubMed id: 29775310

Fragment-Based Discovery of a Potent, Orally Bioavailable Inhibitor That Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

T.D.Heightman, V.Berdini, H.Braithwaite, I.M.Buck, M.Cassidy, J.Castro, A.Courtin, J.E.H.Day, C.East, L.Fazal, B.Graham, C.M.Griffiths-Jones, J.F.Lyons, V.Martins, S.Muench, J.M.Munck, D.Norton, M.O'Reilly, N.Palmer, P.Pathuri, M.Reader, D.C.Rees, S.J.Rich, C.Richardson, H.Saini, N.T.Thompson, N.G.Wallis, H.Walton, N.E.Wilsher, A.J.Woolford, M.Cooke, D.Cousin, S.Onions, J.Shannon, J.Watts, C.W.Murray.

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.