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

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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.

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Most cited references 43

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Hepatocellular carcinoma

Josep Llovet, Robin Kate Kelley, Augusto Villanueva … (2021)

Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.

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Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.

Paul Angulo, David Kleiner, Sanne Dam-Larsen … (2015)

Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.

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Is Open Access

A multisociety Delphi consensus statement on new fatty liver disease nomenclature

Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu … (2023)

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Chem

Journal ID (iso-abbrev): J Med Chem

Journal ID (publisher-id): jm

Journal ID (coden): jmcmar

Title: Journal of Medicinal Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-2623

ISSN (Electronic): 1520-4804

Publication date (Electronic): 12 March 2025

Publication date Collection: 27 March 2025

Volume: 68

Issue: 6

Pages: 6815-6831

Affiliations

[a ]EaStCHEM School of Chemistry, University of Edinburgh , David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.

[b ]BioAscent Discovery Ltd. , Newhouse, Scotland Lanarkshire ML1 5UH, U.K.

[c ]Cytochroma Ltd., Roslin Innovation Centre, Easter Bush Estate , Edinburgh, Scotland EH25 9RG, U.K.

[d ]Concept Life Sciences Ltd. , Nine, 9 Little France Road, Edinburgh Bioquarter, Edinburgh, Scotland EH16 4UX, U.K.

[e ]Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, U.K.

[f ]The Edinburgh Protein Production Facility (EPPF), University of Edinburgh , Level 3 Michael Swann Building, King’s Buildings, Max Born Crescent, Edinburgh, Scotland EH9 3FF, U.K.

[g ]Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh , 4-5 Little France Drive, Edinburgh Bioquarter, Edinburgh, Scotland EH16 4UU, U.K.

Author notes

[* ]Email: julien.michel@ 123456ed.ac.uk .

Author information

Michail Papadourakis https://orcid.org/0000-0002-9969-5871

Alison N. Hulme https://orcid.org/0000-0002-4619-1506

Julien Michel https://orcid.org/0000-0003-0360-1760

Article

DOI: 10.1021/acs.jmedchem.5c00301

PMC ID: 11956012

PubMed ID: 40074291

SO-VID: 9aa29f91-282b-4268-835b-88d9c0bdc040

License:

Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

History

Date received : 30 January 2025

Date accepted : 19 February 2025

Funding

Funded by: H2020 European Research Council, doi 10.13039/100010663;

Award ID: 861942

Custom metadata

document-id-old-9 jm5c00301

document-id-new-14 jm5c00301

ccc-price

ScienceOpen disciplines: Pharmaceutical chemistry

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