2O2N

Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand

Summary for 2O2N

• Entry DOI: 10.2210/pdb2o2n/pdb
• Related: 2O1Y 2O21 2O22 2O2F 2O2M
• Descriptor: Apoptosis regulator Bcl-X, 4-[4-(BIPHENYL-2-YLMETHYL)PIPERAZIN-1-YL]-N-[(4-{[1,1-DIMETHYL-2-(PHENYLTHIO)ETHYL]AMINO}-3-NITROPHENYL)SULFONYL]BENZAMIDE (2 entities in total)
• Functional Keywords: apoptosis, complex, bcl
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion membrane; Single-pass membrane protein (By similarity): Q07817
• Total number of polymer chains: 1
• Total formula weight: 16821.80

Authors

Bruncko, M.,Oost, T.K.,Belli, B.A.,Ding, H.,Joseph, M.K.,Kunzer, A.,Martineau, D.,McClellan, W.J.,Mitten, M.,Ng, S.C.,Nimmer, P.M.,Oltersdorf, T.,Park, C.M.,Petros, A.M.,Shoemaker, A.R.,Song, X.,Wang, X.,Wendt, M.D.,Zhang, H.,Fesik, S.W.,Rosenberg, S.H.,Elmore, S.W. (deposition date: 2006-11-30, release date: 2007-02-27, Last modification date: 2023-12-27)

Primary citation

Bruncko, M.,Oost, T.K.,Belli, B.A.,Ding, H.,Joseph, M.K.,Kunzer, A.,Martineau, D.,McClellan, W.J.,Mitten, M.,Ng, S.C.,Nimmer, P.M.,Oltersdorf, T.,Park, C.M.,Petros, A.M.,Shoemaker, A.R.,Song, X.,Wang, X.,Wendt, M.D.,Zhang, H.,Fesik, S.W.,Rosenberg, S.H.,Elmore, S.W.
Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL.
J.Med.Chem., 50:641-662, 2007

PubMed Abstract: Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

PubMed: 17256834
DOI: 10.1021/jm061152t

Experimental method

SOLUTION NMR