Fungal-selective resorcylate aminopyrazole Hsp90 inhibitors: optimization of whole-cell anticryptococcal activity and insights into the structural origins of cryptococcal selectivity

Marcyk, Paul T.; LeBlanc, Emmanuelle V.; Kuntz, Douglas A.; Xue, Alice; Ortiz, Francisco; Trilles, Richard; Bengtson, Stephen; Kenney, Tristan M. G.; Huang, David S.; Robbins, Nicole; Williams, Noelle S.; Krysan, Damian J.; Privé, Gilbert G.; Whitesell, Luke; Cowen, Leah E.; Brown, Lauren E.

doi:10.1021/acs.jmedchem.0c01777

Cited by 40Heat shock proteins researchFungal Infections and StudiesFungal Plant Pathogen Control

Fungal-selective resorcylate aminopyrazole Hsp90 inhibitors: optimization of whole-cell anticryptococcal activity and insights into the structural origins of cryptococcal selectivity

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Marcyk, Paul T., LeBlanc, Emmanuelle V., Kuntz, Douglas A., Xue, Alice, Ortiz, Francisco, Trilles, Richard, Bengtson, Stephen, Kenney, Tristan M. G. +8 more·2021·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.0c01777PMC PMC8493596

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Abstract

The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many of which govern thermotolerance, virulence, and drug resistance in fungal species. However, use of Hsp90 inhibitors as antifungal therapeutics has been precluded by human host toxicities and suppression of immune responses. We recently described resorcylate aminopyrazoles (RAPs) as the first class of Hsp90 inhibitors capable of discriminating between fungal ( Cryptococcus neoformans, Candida albicans ) and human isoforms of Hsp90 in biochemical assays. Here, we report an iterative structure–property optimization toward RAPs capable of inhibiting C. neoformans growth in culture. In addition, we report the first X-ray crystal structures of C. neoformans Hsp90 nucleotide binding domain (NBD), as the apoprotein and in complexes with the non-species-selective Hsp90 inhibitor NVP-AUY922 and three RAPs revealing unique ligand-induced conformational rearrangements, which reaffirm the hypothesis that intrinsic differences in protein flexibility can confer selective inhibition of fungal versus human Hsp90 isoforms.

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The Hsp90 antibody recognizes two bands, and the top band has been validated as Hsp90 using synthesized C. neoformans Hsp90 protein.
“The Hsp90 antibody recognizes two bands; the top band has been validated as Hsp90 using synthesized C. neoformans Hsp90 protein(Marcyk et al. 2021).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Marcyk et al. 2021

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Pan- and isoform-specific inhibition of Hsp90: Design strategy and recent advances
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Selective Inhibition of the Hsp90α Isoform
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Authors: Marcyk, P. T., LeBlanc, E. V., Kuntz, D. A., Xue, A., Ortiz, F., Trilles, R., Bengtson, S., Kenney, T. M. G., Huang, D. S., Robbins, N., Williams, N. S., Krysan, D. J., Privé, G. G., Whitesell, L., Cowen, L. E., & Brown, L. E.
Affiliations: Boston University (US)
University of Toronto (CA)
Princess Margaret Cancer Centre (CA)
The University of Texas Southwestern Medical Center (US)
University of Iowa (US)
Corresponding author: Privé, Gilbert G.
Whitesell, Luke
Cowen, Leah E.
Brown, Lauren E.
ORCID: Marcyk, Paul T.
LeBlanc, Emmanuelle V.
Kuntz, Douglas A.
Bengtson, Stephen
Kenney, Tristan M. G.
Huang, David S.
Robbins, Nicole
Williams, Noelle S.
Krysan, Damian J.
Privé, Gilbert G.
Whitesell, Luke
Cowen, Leah E.
Brown, Lauren E.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2021-01-14
Volume: 64
Issue: 2
Pages: 1139-1169
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/acs.jmedchem.0c01777
PMC: PMC8493596
OpenAlex: W3118562358
Cited by: 40
References: 92
Citations by year: 2026: 5 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 8
FWCI: 2.51
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Samuel Waxman Cancer Research Foundation
Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI120958)
Natural Sciences and Engineering Research Council of Canada
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords: Hsp90 inhibitors, Cryptococcus neoformans, Candida albicans, structure-activity optimization, X-ray crystal structure, NVP-AUY922, protein flexibility
MeSH terms: Animals, Antifungal Agents, Cell Line, Cell Survival, Cryptococcus neoformans, Fungi, Humans, Microbial Sensitivity Tests, Microsomes, Liver, Protein Binding, Pyrazoles, Species Specificity, Structure-Activity Relationship, Crystallography, X-Ray, HSP90 Heat-Shock Proteins, Mice

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Fungal-selective resorcylate aminopyrazole Hsp90 inhibitors: optimization of whole-cell anticryptococcal activity and insights into the structural origins of cryptococcal selectivity

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