2YI7

Structural characterization of 5-Aryl-4-(5-substituted-2-4- dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors.

Summary for 2YI7

• Entry DOI: 10.2210/pdb2yi7/pdb
• Related: 1BYQ 1OSF 1UY6 1UY7 1UY8 1UY9 1UYC 1UYD 1UYE 1UYF 1UYG 1UYH 1UYI 1UYK 1UYL 1YC1 1YC3 1YC4 1YER 1YES 1YET 2BSM 2BT0 2BUG 2BYH 2BYI 2BZ5 2C2L 2CCS 2CCT 2CCU 2CDD 2FWY 2FWZ 2JJC 2UWD 2VCI 2VCJ 2WI1 2WI2 2WI3 2WI4 2WI5 2WI6 2WI7 2XAB 2XDK 2XDL 2XDS 2XDU 2XDX 2XHR 2XHT 2XHX 2XJG 2XJJ 2XJX 2XK2 2YE2 2YE3 2YE4 2YE5 2YE6 2YE7 2YE8 2YE9 2YEA 2YEB 2YEC 2YED 2YEE 2YEF 2YEG 2YEH 2YEI 2YEJ 2YI0 2YI5 2YI6
• Descriptor: HEAT SHOCK PROTEIN HSP 90-ALPHA, 4-CHLORO-6-[5-(4-ETHOXYPHENYL)-1,2,3-THIADIAZOL-4-YL BENZENE-1,3-DIOL, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: chaperone, atpase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 26229.19

Authors

Roe, S.M.,Prodromou, C.,Pearl, L.H. (deposition date: 2011-05-10, release date: 2012-05-16, Last modification date: 2024-05-01)

Primary citation

Sharp, S.Y.,Roe, S.M.,Kazlauskas, E.,Cikotiene, I.,Workman, P.,Matulis, D.,Prodromou, C.
Co-Crystalization and in Vitro Biological Characterization of 5-Aryl-4-(5-Substituted-2-4-Dihydroxyphenyl)-1,2,3-Thiadiazole Hsp90 Inhibitors.
Plos One, 7:44642-, 2012

PubMed Abstract: A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp90.

PubMed: 22984537
DOI: 10.1371/JOURNAL.PONE.0044642

Experimental method

X-RAY DIFFRACTION (1.4 Å)