Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction

Jakob S. Pallesen; Claire C. Munier; Francesco Bosica; Sebastian A. Andrei; Karl Edman; Anders Gunnarsson; Giuseppina La Sala; Okky Dwichandra Putra; Sonja Srdanović; Andrew J. Wilson; Lisa Wissler; Christian Ottmann; Matthew W.D. Perry; Gavin O'Mahony

doi:10.1021/acs.jmedchem.2c01635

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction

Jakob S. Pallesen
, Claire C. Munier
, Francesco Bosica
, Sebastian A. Andrei
, Karl Edman
, Anders Gunnarsson
, Giuseppina La Sala
, Okky Dwichandra Putra
, Sonja Srdanović
, Andrew J. Wilson
, Lisa Wissler
, Christian Ottmann
, Matthew W.D. Perry
, Gavin O'Mahony^*

^*Corresponding author for this work

Chemistry

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

1 Citation (Scopus)

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Abstract

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.

Original language	English
Pages (from-to)	16818-16828
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	24
Early online date	9 Dec 2022
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01635
Publication status	Published - 22 Dec 2022

Bibliographical note

Funding Information:
This work was supported by the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179. J.P., C.C.M., and G.O’M. acknowledge Dr. Malin Lemurell, AstraZeneca and the AstraZeneca PostDoc program for their financial support.

Copyright:
© 2022The Authors.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Correction to “Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein–Protein Interaction”
Pallesen, J. S., Munier, C. C., Bosica, F., Andrei, S. A., Edman, K., Gunnarsson, A., Sala, G. L., Putra, O. D., Srdanovic, S., Wilson, A. J., Wissler, L., Ottmann, C., Perry, M. W. D. & O Mahony, G., 9 Feb 2023, In: Journal of Medicinal Chemistry. 66, 3, p. 2205-2207 3 p.
Research output: Contribution to journal › Comment/debate › peer-review

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Pallesen, J. S., Munier, C. C., Bosica, F., Andrei, S. A., Edman, K., Gunnarsson, A., La Sala, G., Putra, O. D., Srdanović, S., Wilson, A. J., Wissler, L., Ottmann, C., Perry, M. W. D., & O'Mahony, G. (2022). Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction. Journal of Medicinal Chemistry, 65(24), 16818-16828. https://doi.org/10.1021/acs.jmedchem.2c01635

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title = "Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction",

abstract = "The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.",

author = "Pallesen, \{Jakob S.\} and Munier, \{Claire C.\} and Francesco Bosica and Andrei, \{Sebastian A.\} and Karl Edman and Anders Gunnarsson and \{La Sala\}, Giuseppina and Putra, \{Okky Dwichandra\} and Sonja Srdanovi{\'c} and Wilson, \{Andrew J.\} and Lisa Wissler and Christian Ottmann and Perry, \{Matthew W.D.\} and Gavin O'Mahony",

note = "Funding Information: This work was supported by the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179. J.P., C.C.M., and G.O{\textquoteright}M. acknowledge Dr. Malin Lemurell, AstraZeneca and the AstraZeneca PostDoc program for their financial support. Copyright: {\textcopyright} 2022The Authors.",

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month = dec,

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doi = "10.1021/acs.jmedchem.2c01635",

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Pallesen, JS, Munier, CC, Bosica, F, Andrei, SA, Edman, K, Gunnarsson, A, La Sala, G, Putra, OD, Srdanović, S, Wilson, AJ, Wissler, L, Ottmann, C, Perry, MWD & O'Mahony, G 2022, 'Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction', Journal of Medicinal Chemistry, vol. 65, no. 24, pp. 16818-16828. https://doi.org/10.1021/acs.jmedchem.2c01635

TY - JOUR

T1 - Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction

AU - Pallesen, Jakob S.

AU - Munier, Claire C.

AU - Bosica, Francesco

AU - Andrei, Sebastian A.

AU - Edman, Karl

AU - Gunnarsson, Anders

AU - La Sala, Giuseppina

AU - Putra, Okky Dwichandra

AU - Srdanović, Sonja

AU - Wilson, Andrew J.

AU - Wissler, Lisa

AU - Ottmann, Christian

AU - Perry, Matthew W.D.

AU - O'Mahony, Gavin

N1 - Funding Information: This work was supported by the Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions of the European Commission under Grant Agreement 675179. J.P., C.C.M., and G.O’M. acknowledge Dr. Malin Lemurell, AstraZeneca and the AstraZeneca PostDoc program for their financial support. Copyright: © 2022The Authors.

PY - 2022/12/22

Y1 - 2022/12/22

N2 - The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.

AB - The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein-protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators.

UR - https://www.scopus.com/pages/publications/85143873097

U2 - 10.1021/acs.jmedchem.2c01635

DO - 10.1021/acs.jmedchem.2c01635

M3 - Article

C2 - 36484727

AN - SCOPUS:85143873097

SN - 0022-2623

VL - 65

SP - 16818

EP - 16828

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein-Protein Interaction

Abstract

Bibliographical note

UN SDGs

ASJC Scopus subject areas

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Research output

Correction to “Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein–Protein Interaction”

Cite this