2O2M
Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand
Summary for 2O2M
| Entry DOI | 10.2210/pdb2o2m/pdb |
| Descriptor | Apoptosis regulator Bcl-X, 4-(4-BENZYL-4-METHOXYPIPERIDIN-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 | 16774.75 |
| 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 Cited by 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: 17256834DOI: 10.1021/jm061152t PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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