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

Nanette L.S. Que; Vincent M. Crowley; Adam S. Duerfeldt; Jinbo Zhao; Caitlin N. Kent; Brian S.J. Blagg; Daniel T. Gewirth

doi:10.1021/acs.jmedchem.7b01608

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

Nanette L.S. Que, Vincent M. Crowley, Adam S. Duerfeldt, Jinbo Zhao, Caitlin N. Kent, Brian S.J. Blagg, Daniel T. Gewirth

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2793-2805
Number of pages	13
Journal	Journal of medicinal chemistry
Volume	61
Issue number	7
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01608
State	Published - Apr 12 2018
Externally published	Yes

Bibliographical note

Funding Information:
D.T.G. is funded by grants from the NIH (Grants R01-CA095130, P01-CA186866) and the Richard and Mae Stone Goode Foundation of Buffalo. B.S.J.B. is supported by NIH Grant EY024232, and V.M.C. is supported by Grant F99212467 from the NCI. X-ray diffraction data were collected at the Advanced Photon Source beamlines 23ID-B and 17-ID and the Stanford Synchrotron Radiation Lab beamline BL9-2.

Publisher Copyright:
© 2018 American Chemical Society.

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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.",

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note = "Funding Information: D.T.G. is funded by grants from the NIH (Grants R01-CA095130, P01-CA186866) and the Richard and Mae Stone Goode Foundation of Buffalo. B.S.J.B. is supported by NIH Grant EY024232, and V.M.C. is supported by Grant F99212467 from the NCI. X-ray diffraction data were collected at the Advanced Photon Source beamlines 23ID-B and 17-ID and the Stanford Synchrotron Radiation Lab beamline BL9-2. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

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

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