3WIX
Crystal structure of Mcl-1 in complex with compound 4
Summary for 3WIX
| Entry DOI | 10.2210/pdb3wix/pdb |
| Related | 3WIY 3WIZ |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, 7-(4-carboxyphenyl)-3-[3-(naphthalen-1-yloxy)propyl]pyrazolo[1,5-a]pyridine-2-carboxylic acid (3 entities in total) |
| Functional Keywords | regulation, apoptosis |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass membrane protein (Potential): Q07820 |
| Total number of polymer chains | 4 |
| Total formula weight | 74684.68 |
| 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 Cited by 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: 24215352DOI: 10.1021/jm401170c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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