3DS6

P38 complex with a phthalazine inhibitor

Summary for 3DS6

• Entry DOI: 10.2210/pdb3ds6/pdb
• Descriptor: Mitogen-activated protein kinase 14, N-cyclopropyl-4-methyl-3-[1-(2-methylphenyl)phthalazin-6-yl]benzamide (2 entities in total)
• Functional Keywords: kinase inhibitor complex, alternative splicing, atp-binding, cytoplasm, kinase, nucleotide-binding, nucleus, phosphoprotein, polymorphism, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 4
• Total formula weight: 169569.67

Authors

Herberich, B.,Syed, R.,Li, V.,Grosfeld, D. (deposition date: 2008-07-11, release date: 2008-10-07, Last modification date: 2024-04-03)

Primary citation

Herberich, B.,Cao, G.Q.,Chakrabarti, P.P.,Falsey, J.R.,Pettus, L.,Rzasa, R.M.,Reed, A.B.,Reichelt, A.,Sham, K.,Thaman, M.,Wurz, R.P.,Xu, S.,Zhang, D.,Hsieh, F.,Lee, M.R.,Syed, R.,Li, V.,Grosfeld, D.,Plant, M.H.,Henkle, B.,Sherman, L.,Middleton, S.,Wong, L.M.,Tasker, A.S.
Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
J.Med.Chem., 51:6271-6279, 2008

PubMed Abstract: Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.

PubMed: 18817365
DOI: 10.1021/jm8005417

Experimental method

X-RAY DIFFRACTION (2.9 Å)