Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94 Journal Article


Authors: Patel, H. J.; Patel, P. D.; Ochiana, S. O.; Yan, P.; Sun, W.; Patel, M. R.; Shah, S. K.; Tramentozzi, E.; Brooks, J.; Bolaender, A.; Shrestha, L.; Stephani, R.; Finotti, P.; Leifer, C.; Li, Z.; Gewirth, D. T.; Taldone, T.; Chiosis, G.
Article Title: Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94
Abstract: Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC<inf>50</inf> = 0.22 μM) and selectivity over other paralogs (>100- and 33-fold for Hsp90α/β and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor. © 2015 American Chemical Society.
Journal Title: Journal of Medicinal Chemistry
Volume: 58
Issue: 9
ISSN: 0022-2623
Publisher: American Chemical Society  
Date Published: 2015-05-14
Start Page: 3922
End Page: 3943
Language: English
DOI: 10.1021/acs.jmedchem.5b00197
PROVIDER: scopus
PUBMED: 25901531
PMCID: PMC4518544
DOI/URL:
Notes: Export Date: 3 June 2015 -- Source: Scopus
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MSK Authors
  1. Hardik Jitendra Patel
    27 Patel
  2. Gabriela Chiosis
    279 Chiosis
  3. Tony Taldone
    93 Taldone
  4. Weilin Sun
    16 Sun
  5. Pengrong Yan
    24 Yan
  6. Maulik Rameshchand Patel
    14 Patel
  7. Smit Kamalkumar Shah
    12 Shah
  8. Stefan Ovidiu Ochiana
    15 Ochiana
  9. Pallav D Patel
    15 Patel