7UR3

Hsp90 alpha inhibitor

Summary for 7UR3

• Entry DOI: 10.2210/pdb7ur3/pdb
• Descriptor: Heat shock protein HSP 90-alpha, (5-fluoro-1,3-dihydro-2H-isoindol-2-yl){4-hydroxy-3-[(2S)-2-hydroxy-5-phenylpentan-2-yl]phenyl}methanone (3 entities in total)
• Functional Keywords: chaperone, hsp90, inhibitor, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33919.73

Authors

Deng, J.,Peng, S.,Balch, M.,Matts, R. (deposition date: 2022-04-21, release date: 2022-12-28, Last modification date: 2023-10-25)

Primary citation

Mishra, S.J.,Reynolds, T.S.,Merfeld, T.,Balch, M.,Peng, S.,Deng, J.,Matts, R.,Blagg, B.S.J.
Structure-Activity Relationship Study of Tertiary Alcohol Hsp90 alpha-Selective Inhibitors with Novel Binding Mode.
Acs Med.Chem.Lett., 13:1870-1878, 2022

PubMed Abstract: The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of client proteins associated with all 10 hallmarks of cancer. Herein, the design, synthesis, and biological validation of Hsp90α-selective inhibitors that contain a tertiary alcohol are reported. Forty-one analogues were synthesized to modulate hydrogen-bonding interactions and to probe for steric and hydrophobic interactions within the Hsp90α binding site. Cocrystal structures of lead compound (IC = 0.25 μM, 15-fold selective vs Hsp90β) and a 5-fluoroisoindoline derivative () revealed a novel binding mode that induced conformational changes within Hsp90α's N-terminal domain. The lead Hsp90α-selective inhibitors did not manifest significant antiproliferative activity, but they did result in selective and dose-dependent degradation of Hsp90α clients in the cellular environment. Additional studies will be sought to determine the effects of the novel conformational change induced by .

PubMed: 36518703
DOI: 10.1021/acsmedchemlett.2c00327

Experimental method

X-RAY DIFFRACTION (1.6 Å)