4L94

Crystal structure of Human Hsp90 with S46

Summary for 4L94

• Entry DOI: 10.2210/pdb4l94/pdb
• Related: 4L8Z 4L90 4L91 4L93
• Descriptor: Heat shock protein HSP 90-alpha, (4-hydroxyphenyl)(4-methylpiperazin-1-yl)methanone (3 entities in total)
• Functional Keywords: atp hydrolysis, hsp90n-hsp90n inhibitor complex, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 25877.04

Authors

Li, J.,Ren, J.,Yang, M.,Xiong, B.,He, J. (deposition date: 2013-06-18, release date: 2014-06-18, Last modification date: 2023-11-08)

Primary citation

Ren, J.,Li, J.,Wang, Y.,Chen, W.,Shen, A.,Liu, H.,Chen, D.,Cao, D.,Li, Y.,Zhang, N.,Xu, Y.,Geng, M.,He, J.,Xiong, B.,Shen, J.
Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization
Bioorg.Med.Chem.Lett., 24:2525-2529, 2014

PubMed Abstract: Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20-40 nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs.

PubMed: 24751441
DOI: 10.1016/j.bmcl.2014.03.100

Experimental method

X-RAY DIFFRACTION (1.649 Å)