PDBsum entry 2rg5

Transferase

PDB id: 2rg5

Contents

Protein chain

333 a.a. *

Ligands

279

Waters ×38

* Residue conservation analysis

PDB id:

2rg5

Name:

Transferase

Title:

Phenylalanine pyrrolotriazine p38 alpha map kinase inhibitor compound 11b

Structure:

Mitogen-activated protein kinase 14. Chain: a. Synonym: mitogen-activated protein kinase p38 alpha. Map kinase p38 alpha. Cytokine suppressive anti-inflammatory drug-binding protein. Csaid-binding protein. Csbp. Max-interacting protein 2. Map kinase mxi2. Sapk2a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: bl21 de3.

Resolution:

2.40Å R-factor: 0.240 R-free: 0.305

Authors:

J.S.Sack

Key ref:

J.Hynes et al. (2008). Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors. J Med Chem, 51, 4-16. PubMed id: 18072718

Date:

02-Oct-07 Release date: 15-Jan-08

Protein chain

Q16539  (MK14_HUMAN) -  Mitogen-activated protein kinase 14 from Homo sapiens

Seq: 360 a.a.

Struc: 333 a.a.

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

J Med Chem 51:4-16 (2008)

PubMed id: 18072718

Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors.

J.Hynes, A.J.Dyckman, S.Lin, S.T.Wrobleski, H.Wu, K.M.Gillooly, S.B.Kanner, H.Lonial, D.Loo, K.W.McIntyre, S.Pitt, D.R.Shen, D.J.Shuster, X.Yang, R.Zhang, K.Behnia, H.Zhang, P.H.Marathe, A.M.Doweyko, J.S.Tokarski, J.S.Sack, M.Pokross, S.E.Kiefer, J.A.Newitt, J.C.Barrish, J.Dodd, G.L.Schieven, K.Leftheris.

ABSTRACT

A novel structural class of p38 mitogen-activated protein (MAP) kinase inhibitors consisting of substituted 4-(phenylamino)-pyrrolo[2,1- f][1,2,4]triazines has been discovered. An initial subdeck screen revealed that the oxindole-pyrrolo[2,1- f][1,2,4]triazine lead 2a displayed potent enzyme inhibition (IC 50 60 nM) and was active in a cell-based TNFalpha biosynthesis inhibition assay (IC 50 210 nM). Replacement of the C4 oxindole with 2-methyl-5- N-methoxybenzamide aniline 9 gave a compound with superior p38 kinase inhibition (IC 50 10 nM) and moderately improved functional inhibition in THP-1 cells. Further replacement of the C6 ester of the pyrrolo[2,1- f][1,2,4]triazine with amides afforded compounds with increased potency, excellent oral bioavailability, and robust efficacy in a murine model of acute inflammation (murine LPS-TNFalpha). In rodent disease models of chronic inflammation, multiple compounds demonstrated significant inhibition of disease progression leading to the advancement of 2 compounds 11b and 11j into further preclinical and toxicological studies.