4C52

Crystal structure of Bcl-xL in complex with benzoylurea compound (39b)

Summary for 4C52

• Entry DOI: 10.2210/pdb4c52/pdb
• Related: 4C5D
• Descriptor: BCL-2-LIKE PROTEIN 1, (R)-2-(3-(3-((2,4-DIFLUOROPENYL)ETHYNYL)BENZOYL)-3-PROPYLUREIDO)-3-(ISOBUTYLTHIO) PROPANOIC ACID, SULFATE ION, ... (5 entities in total)
• Functional Keywords: apoptosis
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform Bcl-X(L): Mitochondrion inner membrane : Q07817
• Total number of polymer chains: 2
• Total formula weight: 38258.32

Authors

Roy, M.J.,Brady, R.M.,Lessene, G.,Colman, P.M.,Czabotar, P.E. (deposition date: 2013-09-10, release date: 2014-02-05, Last modification date: 2023-12-20)

Primary citation

Brady, R.M.,Vom, A.,Roy, M.J.,Toovey, N.,Smith, B.J.,Moss, R.M.,Hazis, E.,Huang, D.C.S.,Parisot, J.P.,Yang, H.,Street, I.P.,Colman, P.M.,Czabotar, P.E.,Baell, J.B.,Lessene, G.
De-Novo Designed Library of Benzoylureas as Inhibitors of Bcl-Xl: Synthesis, Structural and Biochemical Characterization.
J.Med.Chem., 57:1323-, 2014

PubMed Abstract: The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 μM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.

PubMed: 24456288
DOI: 10.1021/JM401948B

Experimental method

X-RAY DIFFRACTION (2.049 Å)