Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments

Maria-Eleni Kouridaki; Jonathan Gillespie; John Robinson; Tanya Mathie; Laura Bain; Duncan Mcarthur; Angus Morrison; Daniel b. Greenslade; Michail Papadourakis; Kasia Maj; Kate Cameron; Darryl Turner; Scott p. Webster; Martin a. Wear; Dahlia Doughty-Shenton; Alison n. Hulme; Julien Michel

doi:10.1021/acs.jmedchem.5c00301

Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments

Maria-Eleni Kouridaki, Jonathan Gillespie, John Robinson, Tanya Mathie, Laura Bain, Duncan Mcarthur, Angus Morrison, Daniel b. Greenslade, Michail Papadourakis, Kasia Maj, Kate Cameron, Darryl Turner, Scott p. Webster, Martin a. Wear, Dahlia Doughty-Shenton, Alison n. Hulme, Julien Michel

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

Abstract

Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH).Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure−activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacokinetic profile suitable for further development.

Original language	English
Journal	Journal of Medicinal Chemistry
Early online date	12 Mar 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.5c00301
Publication status	E-pub ahead of print - 12 Mar 2025

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20250312Michel_JMedChemFinal published version, 7.49 MBLicence: Creative Commons: Attribution (CC-BY)

https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00301Licence: Creative Commons: Attribution (CC-BY)

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Kouridaki, M.-E., Gillespie, J., Robinson, J., Mathie, T., Bain, L., Mcarthur, D., Morrison, A., Greenslade, D. B., Papadourakis, M., Maj, K., Cameron, K., Turner, D., Webster, S. P., Wear, M. A., Doughty-Shenton, D., Hulme, A. N., & Michel, J. (2025). Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments. Journal of Medicinal Chemistry. Advance online publication. https://doi.org/10.1021/acs.jmedchem.5c00301

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title = "Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments",

abstract = "Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH).Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure−activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacokinetic profile suitable for further development.",

author = "Maria-Eleni Kouridaki and Jonathan Gillespie and John Robinson and Tanya Mathie and Laura Bain and Duncan Mcarthur and Angus Morrison and Greenslade, {Daniel b.} and Michail Papadourakis and Kasia Maj and Kate Cameron and Darryl Turner and Webster, {Scott p.} and Wear, {Martin a.} and Dahlia Doughty-Shenton and Hulme, {Alison n.} and Julien Michel",

year = "2025",

month = mar,

day = "12",

doi = "10.1021/acs.jmedchem.5c00301",

language = "English",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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Kouridaki, M-E, Gillespie, J, Robinson, J, Mathie, T, Bain, L, Mcarthur, D, Morrison, A, Greenslade, DB, Papadourakis, M, Maj, K, Cameron, K, Turner, D, Webster, SP , Wear, MA , Doughty-Shenton, D , Hulme, AN & Michel, J 2025, 'Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments', Journal of Medicinal Chemistry. https://doi.org/10.1021/acs.jmedchem.5c00301

TY - JOUR

T1 - Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments

AU - Kouridaki, Maria-Eleni

AU - Gillespie, Jonathan

AU - Robinson, John

AU - Mathie, Tanya

AU - Bain, Laura

AU - Mcarthur, Duncan

AU - Morrison, Angus

AU - Greenslade, Daniel b.

AU - Papadourakis, Michail

AU - Maj, Kasia

AU - Cameron, Kate

AU - Turner, Darryl

AU - Webster, Scott p.

AU - Wear, Martin a.

AU - Doughty-Shenton, Dahlia

AU - Hulme, Alison n.

AU - Michel, Julien

PY - 2025/3/12

Y1 - 2025/3/12

N2 - Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH).Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure−activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacokinetic profile suitable for further development.

AB - Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH).Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure−activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacokinetic profile suitable for further development.

U2 - 10.1021/acs.jmedchem.5c00301

DO - 10.1021/acs.jmedchem.5c00301

M3 - Article

SN - 0022-2623

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

ER -

Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments

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