3ZK6

Crystal structure of Bcl-xL in complex with inhibitor (Compound 2).

Summary for 3ZK6

• Entry DOI: 10.2210/pdb3zk6/pdb
• Related: 3ZLN 3ZLO 3ZLR
• Descriptor: BCL-2-LIKE PROTEIN 1, N-(3-(5-(1-(2-(benzo[d]thiazol-2-yl)hydrazono)ethyl)furan-2-yl)phenylsulfonyl)-6-phenylhexanamide (3 entities in total)
• Functional Keywords: apoptosis, inhibitor, bcl-2 family
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion membrane; Single-pass membrane protein: Q07817
• Total number of polymer chains: 2
• Total formula weight: 42715.56

Authors

Czabotar, P.E.,Lessene, G.L.,Smith, B.J.,Colman, P.M. (deposition date: 2013-01-22, release date: 2013-04-24, Last modification date: 2023-12-20)

Primary citation

Lessene, G.L.,Czabotar, P.E.,Sleebs, B.E.,Zobel, K.,Lowes, K.L.,Adams, J.M.,Baell, J.B.,Colman, P.M.,Deshayes, K.,Fairbrother, W.J.,Flygare, J.A.,Gibbons, P.,Kersten, W.J.A.,Kulasegaram, S.,Moss, R.M.,Parisot, J.P.,Smith, B.J.,Street, I.P.,Yang, H.,Huang, D.C.S.,Watson, K.G.
Structure-Guided Design of a Selective Bcl-Xl Inhibitor
Nat.Chem.Biol., 9:390-, 2013

PubMed Abstract: The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X(L)-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X(L) and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X(L) and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X(L) from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X(L) for their sustained growth.

PubMed: 23603658
DOI: 10.1038/NCHEMBIO.1246

Experimental method

X-RAY DIFFRACTION (2.48 Å)