The lysyl oxidase like 2/3 enzymatic inhibitor, PXS‐5153A, reduces crosslinks and ameliorates fibrosis

Schilter, Heidi; Findlay, Alison D.; Perryman, Lara; Yow, Tin T; Moses, Joshua; Zahoor, Amna; Turner, Catherine; Deodhar, Mandar; Foot, Jonathan S.; Zhou, Wenbin; Gréco, Angelique; Joshi, Amar; Rayner, Benjamin S.; Townsend, Sarah; Buson, Alberto; Jarolimek, Wolfgang

doi:10.1111/jcmm.14074

Cited by 84 publications

(67 citation statements)

References 52 publications

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“…These include Pharmakea's PAT-1251 (anti-LOXL2) and several inhibitors developed by Pharmaxis with pan-LOX, LOXL2/3, or LOX/LOXL2 specificities. (43,46,57,58) These new molecules are promising antifibrotic agents. Thus, in contrast to antibody, they are orally available and can more easily reach intracellular and dense extracellular compartments, as found in advanced fibrosis.…”

Section: Small-molecule Inhibitorsmentioning

confidence: 99%

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Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

et al. 2020

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The cross‐linking of structural extracellular matrix (ECM) components, especially fibrillar collagens and elastin, is strongly implicated in fibrosis progression and resistance to fibrosis reversal. Lysyl oxidase family members (LOX and LOXL1 [lysyl oxidase‐like 1], LOXL2 [lysyl oxidase‐like 2], LOXL3 [lysyl oxidase‐like 3], and LOXL4 [lysyl oxidase like 4]) are extracellular copper‐dependent enzymes that play a key role in ECM cross‐linking, but have also other intracellular functions relevant to fibrosis and carcinogenesis. Although the expression of most LOX family members is elevated in experimental liver fibrosis of diverse etiologies, their individual contribution to fibrosis is incompletely understood. Inhibition of the LOX family as a whole and of LOX, LOXL1, and LOXL2 specifically has been shown to suppress fibrosis progression and accelerate its reversal in rodent models of cardiac, renal, pulmonary, and liver fibrosis. Recent disappointing clinical trials with a monoclonal antibody against LOXL2 (simtuzumab) in patients with pulmonary and liver fibrosis dampened enthusiasm for LOX family member inhibition. However, this unexpected negative outcome may be related to the inefficient antibody, rather than to LOXL2, not qualifying as a relevant antifibrotic target. Moreover, LOX family members other than LOXL2 may prove to be attractive therapeutic targets. In this review, we summarize the structural hallmarks, expression patterns, covalent cross‐linking activities, and modes of regulation of LOX family members and discuss the clinical potential of their inhibition to treat fibrosis in general and liver fibrosis in particular.

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Section: Small-molecule Inhibitorsmentioning

confidence: 99%

“…Thus, in contrast to antibody, they are orally available and can more easily reach intracellular and dense extracellular compartments, as found in advanced fibrosis. (43,46,57,58)…”

Section: Small-molecule Inhibitorsmentioning

confidence: 99%

Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

et al. 2020

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“…Besides monoclonal antibodies, efforts have been made for developing small-molecules that directly inhibit LOXL2 catalytic activity [89]. PXS-5153A, a novel dual LOXL2/LOXL3 inhibitor, dose-dependently decreased LOXL2-mediated collagen oxidation and CCL in vitro, and improved cardiac output after MI in mice [90]. Abbreviations: BAPN, β-aminopropionitrile (a pan-LOX inhibitor); EF, ejection fraction; FS, fractional shortening; HFD, high fat diet; LAD, left anterior descending; LV, left ventricular; MI, myocardial infarction.…”

Section: Lox/loxls As Pharmacological Targets In Myocardial Diseasesmentioning

confidence: 99%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1-4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter-and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders. part of the mechanoresponsive gene programs responsible for the mechanical regulation of gene expression in cardiac myocytes and fibroblasts [11]. Thus, LOX/LOXLs contribute to cardiac fibrosis, but are also active players involved in the cellular mechanisms underlying cardiac dysfunction and disease progression.In the last years, multiple studies have contributed to the understanding of the pathophysiological role of the LOX family in human diseases and, in particular, in the cardiovascular system. The involvement of this family on vascular diseases has been recently reviewed [12]. Further, LOX/LOXLs participate in a variety of processes affecting the heart, from those associated to post-myocardial infarction (MI) cardiac remodeling, cardiac hypertrophy triggered by pressure or volume overload, heart failure (HF) with preserved ejection fraction (HFPEF) associated with obesity and metabolic syndrome or atrial fibrillation. The strong impact of the alteration of LOX/LOXLs on CCL and heart function supports the interest of these family of enzymes as pharmacological targets to improve cardiac remodeling and slow the progression to HF. In this review article we focus on those findings that support the fundamental involvement of the LOX family in the mechanisms underlying cardiac damage and repair. The LOX Family of ECM-Modifying EnzymesLOX is an extracellular enzyme which governs the post-translational modification of ECM collagen and elastin. LOX catalyzes the oxidative deamination of specific ε-amino groups of lysine and hydroxylysine residues in collagen and elastin. This leads to the generation of highly reactive peptidyl α-aminoadipic γ-semialdehydes and the release of hydrogen peroxide as by-product [1-3] (Figure 1). This reactio...

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“…This was confirmed by Torregrosa-Carrión et al (2019), who reported that NOTCH activation led to increased expression of TGF-β2 and collagen, which form part of the LOXL2 signaling pathway [ 78 ]. Lastly, it was shown by Schilter et al (2019) that administration of a LOXL2 inhibitor for 4-weeks, after left coronary arteries occlusion, resulted in an observed decreased myocardial fibrosis with improved cardiac output in a C57/BL6 mouse model [ 79 ]. Although there is data linking LOXL2 to fibrosis, its regulation in the fibrotic cardiac disease pathophysiology remains ill-defined, and as such, more research is required to better define LOXL2′s mechanistic role in cardiac tissue fibrosis and subsequent contractile dysfunction.…”

Section: Loxl2 In Diseasementioning

confidence: 99%

Linking LOXL2 to Cardiac Interstitial Fibrosis

Erasmus

Samodien

Lecour

et al. 2020

IJMS

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Cardiovascular diseases (CVDs) are the leading causes of death worldwide. CVD pathophysiology is often characterized by increased stiffening of the heart muscle due to fibrosis, thus resulting in diminished cardiac function. Fibrosis can be caused by increased oxidative stress and inflammation, which is strongly linked to lifestyle and environmental factors such as diet, smoking, hyperglycemia, and hypertension. These factors can affect gene expression through epigenetic modifications. Lysyl oxidase like 2 (LOXL2) is responsible for collagen and elastin cross-linking in the heart, and its dysregulation has been pathologically associated with increased fibrosis. Additionally, studies have shown that, LOXL2 expression can be regulated by DNA methylation and histone modification. However, there is a paucity of data on LOXL2 regulation and its role in CVD. As such, this review aims to gain insight into the mechanisms by which LOXL2 is regulated in physiological conditions, as well as determine the downstream effectors responsible for CVD development.

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The lysyl oxidase like 2/3 enzymatic inhibitor, PXS‐5153A, reduces crosslinks and ameliorates fibrosis

Cited by 84 publications

References 52 publications

Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Linking LOXL2 to Cardiac Interstitial Fibrosis

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