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J Med Chem. 2018 Apr 12;61(7):2793-2805. doi: 10.1021/acs.jmedchem.7b01608. Epub 2018 Mar 20.

Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.

Author information

1
Hauptman-Woodward Medical Research Institute , Buffalo , New York 14203 , United States.
2
Department of Medicinal Chemistry , The University of Kansas , Lawrence , Kansas 66045 , United States.
3
Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States.
4
Department of Structural Biology , University at Buffalo , Buffalo , New York 14203 , United States.

Abstract

Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94.

PMID:
29528635
PMCID:
PMC5897183
DOI:
10.1021/acs.jmedchem.7b01608
[Indexed for MEDLINE]
Free PMC Article

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