PDBsum entry 3og7

Transferase/transferase inhibitor

PDB id: 3og7

Contents

Protein chains

247 a.a. *

Ligands

032

Waters ×65

* Residue conservation analysis

PDB id:

3og7

Name:

Transferase/transferase inhibitor

Title:

B-raf kinase v600e oncogenic mutant in complex with plx4032

Structure:

Akap9-braf fusion protein. Chain: a, b. Fragment: kinase domain (unp residues 1175-1446). Synonym: proto-oncogene b-raf, p94, v-raf murine sarcoma viral oncogene homolog b1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: braf, braf1, rafb1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.45Å R-factor: 0.214 R-free: 0.258

Authors:

Y.Zhang,K.Y.Zhang,C.Zhang

Key ref:

G.Bollag et al. (2010). Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 467, 596-599. PubMed id: 20823850

Date:

16-Aug-10 Release date: 22-Sep-10

Protein chains

P15056  (BRAF_HUMAN) -  Serine/threonine-protein kinase B-raf from Homo sapiens

Seq: 766 a.a.

Struc: 247 a.a.*

* PDB and UniProt seqs differ at 14 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine 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

Nature 467:596-599 (2010)

PubMed id: 20823850

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.

G.Bollag, P.Hirth, J.Tsai, J.Zhang, P.N.Ibrahim, H.Cho, W.Spevak, C.Zhang, Y.Zhang, G.Habets, E.A.Burton, B.Wong, G.Tsang, B.L.West, B.Powell, R.Shellooe, A.Marimuthu, H.Nguyen, K.Y.Zhang, D.R.Artis, J.Schlessinger, F.Su, B.Higgins, R.Iyer, K.D'Andrea, A.Koehler, M.Stumm, P.S.Lin, R.J.Lee, J.Grippo, I.Puzanov, K.B.Kim, A.Ribas, G.A.McArthur, J.A.Sosman, P.B.Chapman, K.T.Flaherty, X.Xu, K.L.Nathanson, K.Nolop.

ABSTRACT

B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.