4LWH

Crystal Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor FJ5

Summary for 4LWH

• Entry DOI: 10.2210/pdb4lwh/pdb
• Related: 4LWE 4LWF 4LWG 4LWI
• Descriptor: Heat shock protein HSP 90-alpha, N-{3-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazol-5-yl}cyclopropanecarboxamide (3 entities in total)
• Functional Keywords: rossmann fold, atp binding, molecularchaperone, chaperone
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 1
• Total formula weight: 23870.07

Authors

Li, J.,Shi, F.,Xiong, B.,He, J. (deposition date: 2013-07-27, release date: 2014-07-30, Last modification date: 2023-11-08)

Primary citation

Chen, D.,Shen, A.,Li, J.,Shi, F.,Chen, W.,Ren, J.,Liu, H.,Xu, Y.,Wang, X.,Yang, X.,Sun, Y.,Yang, M.,He, J.,Wang, Y.,Zhang, L.,Huang, M.,Geng, M.,Xiong, B.,Shen, J.
Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.
Eur.J.Med.Chem., 87:765-781, 2014

PubMed 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.

PubMed: 25313505
DOI: 10.1016/j.ejmech.2014.09.065

Experimental method

X-RAY DIFFRACTION (1.7 Å)