Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity—Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases
Graphical abstract
Section snippets
Acknowledgments
The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.
References and notes (27)
- et al.
Adv. Protein Chem.
(2001) - et al.
J. Biol. Chem.
(2012) - et al.
Genomics
(2005) - et al.
Chem. Biol.
(2003) - et al.
Chem. Biol.
(2004) - et al.
J. Biol. Chem.
(2003) - et al.
Mol. Cell
(2007) - et al.
Cell
(1997) - et al.
Exp. Biol. Med.
(2003) - et al.
Curr. Top. Med. Chem.
(2008)
Curr. Top. Med. Chem.
J. Med. Chem.
J. Mol. Med.
Cited by (48)
Following the design path of isoform-selective Hsp90 inhibitors: Small differences, great opportunities
2023, Pharmacology and TherapeuticsTargeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development
2023, Cell Chemical BiologyPan- and isoform-specific inhibition of Hsp90: Design strategy and recent advances
2022, European Journal of Medicinal ChemistryCitation Excerpt :The improved physicochemical and pharmacokinetic properties suggest the further investigation of compound 103 as an anti-inflammatory agent for treating ulcerative colitis [177]. Compared to SNX-2112 (Hsp90α Ki = 4 nM; Hsp90β Ki = 6 nM; Grp94 Ki = 484 nM; Trap1 Ki = 791 nM), compound 104 (SNX-0723) showed improved selectivity for Hsp90α and Hsp90β, over Trap1 and Grp94 (Hsp90α Ki = 3 nM; Hsp90β Ki = 4 nM; Grp94 Ki = 375 nM; Trap1 Ki = 1195 nM) [69]. SNX-0723 could be absorbed by brain tissue efficiently, prevented α-Synuclein oligomerization and rescued striatal dopamine levels associated with parkinsonism [178,179].
2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents
2021, European Journal of Medicinal ChemistryCitation Excerpt :In humans, Hsp90 exists as four isoforms: Hsp90α, Hsp90β, glucose-regulated protein 94 kDa (Grp94), and tumor necrosis receptor-associated protein 1 (Trap1) [14]. Hsp90α and Hsp90β are localized to the cytoplasm, whereas Grp94 resides in the endoplasmic reticulum, and Trap1 is localized within the mitochondria [15]. Most Hsp90 inhibitors are pan-inhibitors that target both cytosolic isoforms (Hsp90α and Hsp90β) [16].
Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery
2020, Acta Pharmaceutica Sinica BCitation Excerpt :The pan-HSP90 inhibitors cannot induce the extended α-helix conformation, so they exhibit similar activity against HSP90, GRP94 and TRAP143. While, based on the sequential difference of HSP90α/β, structural insights for the design of inhibitors with improved HSP90α/β selectivity have been provided44. TAS-116, an HSP90α/β selective inhibitor which was developed through fragment-based drug design by Taiho Pharmaceutical Co., Ltd., has been entered into clinical trials.