The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement
Abstract Cardiac remodeling involves myocardial hypertrophy and fibrosis which impairs cardiac function and, ultimately, contributes to heart failure (HF) and mortality. Fibrosis largely develops due to excessive matrix deposition and lysyl oxidase(s)-dependent collagen cross-linking. In particular,...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-06312-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849769162887397376 |
|---|---|
| author | Lara Perryman Alison Findlay Jana Baskar Brett Charlton Jonathan Foot Ross Hamilton Dieter Hamprecht Amar Joshi Jessica Stolp Craig Turner Amna Zahoor Wenbin Zhou Begoña López Susana Ravassa Arantxa González Wolfgang Jarolimek |
| author_facet | Lara Perryman Alison Findlay Jana Baskar Brett Charlton Jonathan Foot Ross Hamilton Dieter Hamprecht Amar Joshi Jessica Stolp Craig Turner Amna Zahoor Wenbin Zhou Begoña López Susana Ravassa Arantxa González Wolfgang Jarolimek |
| author_sort | Lara Perryman |
| collection | DOAJ |
| description | Abstract Cardiac remodeling involves myocardial hypertrophy and fibrosis which impairs cardiac function and, ultimately, contributes to heart failure (HF) and mortality. Fibrosis largely develops due to excessive matrix deposition and lysyl oxidase(s)-dependent collagen cross-linking. In particular, lysyl oxidase-like 2 (LOXL2) has a critical role in disease progression, representing a promising therapeutic target and rationale for the development of novel, efficacious LOXL2 inhibitor(s). Herein, we describe the pre-clinical validation of a potent small molecule LOXL2 inhibitor as an anti-fibrotic agent, along with its clinical suitability, as high levels of target engagement were sustained in Phase 1 clinical trials while also being well tolerated. We show that LOXL2 concentration is increased in the plasma of patients with HF due to existing hypertension or aortic stenosis. Plasma LOXL2 concentration were correlated with the left ventricular mass index. A novel LOXL2 inhibitor, SNT-5382, was characterised, including in vitro and in vivo assessment of potency and mode of action, which showed beneficial drug-like properties. Preclinically, SNT-5382 reduced fibrosis and improved cardiac function in a myocardial infarction (MI) mouse model. Phase 1 clinical studies demonstrated a good safety and a PK profile capable of eliciting high and prolonged LOXL2 inhibition following repeated once daily oral dosing. Our findings underscore the pivotal role of LOXL2 in the development of HF. SNT-5382 exhibited potent anti-fibrotic efficacy in a MI model and sustained clinical target engagement. Trial registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12617001564347. Registered 21 November 2017- registered, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617001564347 |
| format | Article |
| id | doaj-art-edfd80e5872b411daeac90b48295ab13 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-edfd80e5872b411daeac90b48295ab132025-08-20T03:03:32ZengNature PortfolioScientific Reports2045-23222025-07-0115111210.1038/s41598-025-06312-2The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagementLara Perryman0Alison Findlay1Jana Baskar2Brett Charlton3Jonathan Foot4Ross Hamilton5Dieter Hamprecht6Amar Joshi7Jessica Stolp8Craig Turner9Amna Zahoor10Wenbin Zhou11Begoña López12Susana Ravassa13Arantxa González14Wolfgang Jarolimek15SyntaraSyntaraSyntaraSyntaraSyntaraSyntaraSyntaraSyntaraSyntaraSyntaraSyntaraSyntaraProgram of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA Program of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA Program of Cardiovascular Diseases, CIMA Universidad de Navarra and IdiSNA SyntaraAbstract Cardiac remodeling involves myocardial hypertrophy and fibrosis which impairs cardiac function and, ultimately, contributes to heart failure (HF) and mortality. Fibrosis largely develops due to excessive matrix deposition and lysyl oxidase(s)-dependent collagen cross-linking. In particular, lysyl oxidase-like 2 (LOXL2) has a critical role in disease progression, representing a promising therapeutic target and rationale for the development of novel, efficacious LOXL2 inhibitor(s). Herein, we describe the pre-clinical validation of a potent small molecule LOXL2 inhibitor as an anti-fibrotic agent, along with its clinical suitability, as high levels of target engagement were sustained in Phase 1 clinical trials while also being well tolerated. We show that LOXL2 concentration is increased in the plasma of patients with HF due to existing hypertension or aortic stenosis. Plasma LOXL2 concentration were correlated with the left ventricular mass index. A novel LOXL2 inhibitor, SNT-5382, was characterised, including in vitro and in vivo assessment of potency and mode of action, which showed beneficial drug-like properties. Preclinically, SNT-5382 reduced fibrosis and improved cardiac function in a myocardial infarction (MI) mouse model. Phase 1 clinical studies demonstrated a good safety and a PK profile capable of eliciting high and prolonged LOXL2 inhibition following repeated once daily oral dosing. Our findings underscore the pivotal role of LOXL2 in the development of HF. SNT-5382 exhibited potent anti-fibrotic efficacy in a MI model and sustained clinical target engagement. Trial registration: Australian New Zealand Clinical Trials Registry identifier: ACTRN12617001564347. Registered 21 November 2017- registered, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617001564347https://doi.org/10.1038/s41598-025-06312-2Heart failureLysyl oxidasesLOXL2 small molecule inhibitorAnti-fibrotic therapyFibrosis |
| spellingShingle | Lara Perryman Alison Findlay Jana Baskar Brett Charlton Jonathan Foot Ross Hamilton Dieter Hamprecht Amar Joshi Jessica Stolp Craig Turner Amna Zahoor Wenbin Zhou Begoña López Susana Ravassa Arantxa González Wolfgang Jarolimek The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement Scientific Reports Heart failure Lysyl oxidases LOXL2 small molecule inhibitor Anti-fibrotic therapy Fibrosis |
| title | The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement |
| title_full | The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement |
| title_fullStr | The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement |
| title_full_unstemmed | The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement |
| title_short | The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement |
| title_sort | small molecule loxl2 inhibitor snt 5382 reduces cardiac fibrosis and achieves strong clinical target engagement |
| topic | Heart failure Lysyl oxidases LOXL2 small molecule inhibitor Anti-fibrotic therapy Fibrosis |
| url | https://doi.org/10.1038/s41598-025-06312-2 |
| work_keys_str_mv | AT laraperryman thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT alisonfindlay thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT janabaskar thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT brettcharlton thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT jonathanfoot thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT rosshamilton thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT dieterhamprecht thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT amarjoshi thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT jessicastolp thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT craigturner thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT amnazahoor thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT wenbinzhou thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT begonalopez thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT susanaravassa thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT arantxagonzalez thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT wolfgangjarolimek thesmallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT laraperryman smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT alisonfindlay smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT janabaskar smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT brettcharlton smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT jonathanfoot smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT rosshamilton smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT dieterhamprecht smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT amarjoshi smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT jessicastolp smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT craigturner smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT amnazahoor smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT wenbinzhou smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT begonalopez smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT susanaravassa smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT arantxagonzalez smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement AT wolfgangjarolimek smallmoleculeloxl2inhibitorsnt5382reducescardiacfibrosisandachievesstrongclinicaltargetengagement |