4EHR

Crystal structure of Bcl-Xl complex with 4-(5-butyl-3-(hydroxymethyl)-1-phenyl-1h-pyrazol-4-yl)-3-(3,4-dihydro-2(1h)-isoquinolinylcarbonyl)-n-((2-(trimethylsilyl)ethyl)sulfonyl)benzamide

Summary for 4EHR

• Entry DOI: 10.2210/pdb4ehr/pdb
• Descriptor: Bcl-2-like protein 1, 4-[5-butyl-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-4-yl]-3-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)-N-{[2-(trimethylsilyl)ethyl]sulfonyl}benzamide, IMIDAZOLE, ... (4 entities in total)
• Functional Keywords: apoptosis, programmed cell death, bcl-2 family
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion membrane; Single-pass membrane protein: Q07817
• Total number of polymer chains: 1
• Total formula weight: 20337.49

Authors

Schroeder, G.M.,Wei, D.,Banfi, P.,Cai, Z.,Lippy, J.,Menichincheri, M.,Modugno, M.,Naglich, J.,Penhallow, B.,Perez, H.L.,Sack, J.,Schmidt, R.J.,Tebben, A.,Yan, C.,Zhang, L.,Galvani, A.,Lombardo, L.J.,Borzilleri, R.M. (deposition date: 2012-04-03, release date: 2012-06-06, Last modification date: 2024-02-28)

Primary citation

Schroeder, G.M.,Wei, D.,Banfi, P.,Cai, Z.W.,Lippy, J.,Menichincheri, M.,Modugno, M.,Naglich, J.,Penhallow, B.,Perez, H.L.,Sack, J.,Schmidt, R.J.,Tebben, A.,Yan, C.,Zhang, L.,Galvani, A.,Lombardo, L.J.,Borzilleri, R.M.
Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.
Bioorg.Med.Chem.Lett., 22:3951-3956, 2012

PubMed Abstract: 5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.

PubMed: 22608393
DOI: 10.1016/j.bmcl.2012.04.106

Experimental method

X-RAY DIFFRACTION (2.09 Å)