Journal Article

The small molecule LOXL2 inhibitor SNT-5382 reduces cardiac fibrosis and achieves strong clinical target engagement

Zhou, Wenbin, Hamprecht, Dieter, Stolp, Jessica, Baskar, Jana, Perryman, Lara, López, Begoña, Findlay, Alison, Ravassa, Susana, González, Arantxa, Foot, Jonathan, Hamilton, Ross, Joshi, Amar, Jarolimek, Wolfgang, Charlton, Brett, Zahoor, Amna, Turner, Craig

2025

Overview

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

• Publisher: Nature Publishing Group UK,Nature Portfolio
• Subject: 631/154 / 692/4019 / Aged / Amino Acid Oxidoreductases - antagonists & inhibitors / Amino Acid Oxidoreductases - blood / Amino Acid Oxidoreductases - metabolism / Animals / Anti-fibrotic therapy / Disease Models, Animal / Enzyme Inhibitors - pharmacokinetics / Enzyme Inhibitors - pharmacology / Female / Fibrosis / Fibrosis - drug therapy / Heart failure / Heart Failure - drug therapy / Heart Failure - pathology / Humanities and Social Sciences / Humans / LOXL2 small molecule inhibitor / Lysyl oxidases / Male / Mice / Middle Aged / multidisciplinary / Myocardial Infarction - drug therapy / Myocardial Infarction - pathology / Myocardium - pathology / Science / Science (multidisciplinary)