3BYM

X-ray co-crystal structure aminobenzimidazole triazine 1 bound to Lck

Summary for 3BYM

• Entry DOI: 10.2210/pdb3bym/pdb
• Related: 3BYO
• Descriptor: Proto-oncogene tyrosine-protein kinase LCK, SULFATE ION, N-phenyl-1-{4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazin-2-yl}-1H-benzimidazol-2-amine, ... (4 entities in total)
• Functional Keywords: lck, kinase domain, alternative splicing, atp-binding, chromosomal rearrangement, cytoplasm, disease mutation, host-virus interaction, lipoprotein, membrane, myristate, nucleotide-binding, palmitate, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P06239
• Total number of polymer chains: 1
• Total formula weight: 32215.61

Authors

Huang, X. (deposition date: 2008-01-16, release date: 2008-09-16, Last modification date: 2024-10-30)

Primary citation

Martin, M.W.,Newcomb, J.,Nunes, J.J.,Boucher, C.,Chai, L.,Epstein, L.F.,Faust, T.,Flores, S.,Gallant, P.,Gore, A.,Gu, Y.,Hsieh, F.,Huang, X.,Kim, J.L.,Middleton, S.,Morgenstern, K.,Oliveira-dos-Santos, A.,Patel, V.F.,Powers, D.,Rose, P.,Tudor, Y.,Turci, S.M.,Welcher, A.A.,Zack, D.,Zhao, H.,Zhu, L.,Zhu, X.,Ghiron, C.,Ermann, M.,Johnston, D.,Saluste, C.G.
Structure-based design of novel 2-amino-6-phenyl-pyrimido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): synthesis, SAR, and in vivo anti-inflammatory activity.
J.Med.Chem., 51:1637-1648, 2008

PubMed Abstract: Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.

PubMed: 18278858
DOI: 10.1021/jm701095m

Experimental method

X-RAY DIFFRACTION (2 Å)