PDBsum entry 4lwi

Chaperone

PDB id: 4lwi

Contents

Protein chain

207 a.a.

Ligands

FJ6

Waters ×110

PDB id:

4lwi

Name:

Chaperone

Title:

Crystal structure of the human hsp90-alpha n-domain bound to the hsp90 inhibitor fj6

Structure:

Heat shock protein hsp 90-alpha. Chain: a. Fragment: unp residues 17-224. Synonym: heat shock 86 kda, hsp 86, hsp86, renal carcinoma antigen ny-ren-38. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hsp90aa1, hsp90a, hspc1, hspca. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.70Å R-factor: 0.192 R-free: 0.213

Authors:

J.Li,F.Shi,B.Xiong,J.He

Key ref:

D.Chen et al. (2014). Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors. Eur J Med Chem, 87, 765-781. PubMed id: 25313505 DOI: 10.1016/j.ejmech.2014.09.065

Date:

27-Jul-13 Release date: 30-Jul-14

Protein chain

P07900  (HS90A_HUMAN) -  Heat shock protein HSP 90-alpha from Homo sapiens

Seq: 732 a.a.

Struc: 207 a.a.

Enzyme reactions

• Enzyme class: E.C.3.6.4.10 - non-chaperonin molecular chaperone ATPase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2014.09.065

Eur J Med Chem 87:765-781 (2014)

PubMed id: 25313505

Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.

D.Chen, A.Shen, J.Li, F.Shi, W.Chen, J.Ren, H.Liu, Y.Xu, X.Wang, X.Yang, Y.Sun, M.Yang, J.He, Y.Wang, L.Zhang, M.Huang, M.Geng, B.Xiong, J.Shen.

ABSTRACT

HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.