2WI3

Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone

Summary for 2WI3

• Entry DOI: 10.2210/pdb2wi3/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 2JJC 2UWD 2VCI 2VCJ 2WI1 2WI2 2WI4 2WI5 2WI6 2WI7
• Descriptor: HEAT SHOCK PROTEIN, HSP 90-ALPHA, MAGNESIUM ION, 4-METHYL-6-(METHYLSULFANYL)-1,3,5-TRIAZIN-2-AMINE, ... (4 entities in total)
• Functional Keywords: chaperone, heat shock, stress response, nucleotide-binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 26782.29

Authors

Brough, P.A.,Barril, X.,Borgognoni, J.,Chene, P.,Davies, N.G.M.,Davis, B.,Drysdale, M.J.,Dymock, B.,Eccles, S.A.,Garcia-Echeverria, C.,Fromont, C.,Hayes, A.,Hubbard, R.E.,Jordan, A.M.,Rugaard-Jensen, M.,Massey, A.,Merret, A.,Padfield, A.,Parsons, R.,Radimerski, T.,Raynaud, F.I.,Robertson, A.,Roughley, S.D.,Schoepfer, J.,Simmonite, H.,Surgenor, A.,Valenti, M.,Walls, S.,Webb, P.,Wood, M.,Workman, P.,Wright, L.M. (deposition date: 2009-05-08, release date: 2009-07-28, Last modification date: 2023-12-13)

Primary citation

Brough, P.A.,Barril, X.,Borgognoni, J.,Chene, P.,Davies, N.G.M.,Davis, B.,Drysdale, M.J.,Dymock, B.,Eccles, S.A.,Garcia-Echeverria, C.,Fromont, C.,Hayes, A.,Hubbard, R.E.,Jordan, A.M.,Jensen, M.R.,Massey, A.,Merrett, A.,Padfield, A.,Parsons, R.,Radimerski, T.,Raynaud, F.I.,Robertson, A.,Roughley, S.D.,Schoepfer, J.,Simmonite, H.,Sharp, S.Y.,Surgenor, A.,Valenti, M.,Walls, S.,Webb, P.,Wood, M.,Workman, P.,Wright, L.M.
Combining Hit Identification Strategies: Fragment- Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-D]Pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.
J.Med.Chem., 52:4794-, 2009

PubMed Abstract: Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

PubMed: 19610616
DOI: 10.1021/JM900357Y

Experimental method

X-RAY DIFFRACTION (1.9 Å)