3WIZ

Crystal structure of Bcl-xL in complex with compound 10

Summary for 3WIZ

• Entry DOI: 10.2210/pdb3wiz/pdb
• Related: 3WIX 3WIY
• Descriptor: Bcl-2-like protein 1, 7-(4-{[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrophenyl)sulfonyl]carbamoyl}-2-methylphenyl)-3-[3-(naphthalen-1-yloxy)propyl]pyrazolo[1,5-a]pyridine-2-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: regulation, apoptosis
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform Bcl-X(L): Mitochondrion inner membrane : Q07817
• Total number of polymer chains: 2
• Total formula weight: 42732.75

Authors

Sogabe, S.,Igaki, S.,Hayano, Y. (deposition date: 2013-09-26, release date: 2013-11-27, Last modification date: 2023-11-08)

Primary citation

Tanaka, Y.,Aikawa, K.,Nishida, G.,Homma, M.,Sogabe, S.,Igaki, S.,Hayano, Y.,Sameshima, T.,Miyahisa, I.,Kawamoto, T.,Tawada, M.,Imai, Y.,Inazuka, M.,Cho, N.,Imaeda, Y.,Ishikawa, T.
Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins.
J.Med.Chem., 56:9635-9645, 2013

PubMed Abstract: Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A cocrystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein-ligand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. On the basis of the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC50 = 0.088 μM; and Bcl-xL, IC50 = 0.0037 μM).

PubMed: 24215352
DOI: 10.1021/jm401170c

Experimental method

X-RAY DIFFRACTION (2.45 Å)