An activity‐based bioprobe differentiates a novel small molecule inhibitor from a LOXL2 antibody and provides renewed promise for anti‐fibrotic therapeutic strategies

Findlay, Alison D.; Turner, Catherine; Schilter, Heidi; Deodhar, Mandar; Zhou, Wenbin; Perryman, Lara; Foot, Jonathan S.; Zahoor, Amna; Yao, Yanhua; Hamilton, R.; Brock, Mary Jane; Raso, Christina; Stolp, Jessica; Galati, Marie; Hamprecht, Dieter; Charlton, Brett; Jarolimek, Wolfgang

doi:10.1002/ctm2.572

Cited by 15 publications

(20 citation statements)

References 10 publications

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“…The physical properties of the scar were affected, but insufficient data was collected to conclude a therapeutic effect [ 162 ]. BAPN is not considered to be a clinical candidate due to the potential of bone changes and off- target effects [ 160 , 163 ]. BAPN is also a substrate for the other amine oxidases (semi carbazide-sensitive amine oxidase (SSAO) and diamine oxidase (DAO), which may contribute to the side effects observed in clinical trials [ 160 ].…”

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

“…However, in the clinic, despite Simtuzumab being well-tolerated, it did not show efficacy in both cancers and fibrotic diseases ( Table 3 ). The lack of efficacy of Simtuzumab is thought to be dependent on a number of factors—which are irrespective of the potential of targeting the lysyl oxidase family in cancer and fibrotic diseases [ 160 ].…”

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

“…For example, all current trials are wielding oral small-molecule enzymatic inhibitors, which should be optimal for tissue penetration ( Table 3 ). Furthermore, target engagement assays have been developed utilizing Quanterix technology to measure low concentrations and activity of LOX and LOXL2 specifically, in both tissue and plasma [ 160 ]. The plasma LOX and LOXL2 activity has been shown to mirror recovery of activity in human tissue, providing a less invasive monitoring of target engagement.…”

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

“…The plasma LOX and LOXL2 activity has been shown to mirror recovery of activity in human tissue, providing a less invasive monitoring of target engagement. The establishment of target engagement assays has illustrated the dynamic nature of protein resynthesis, particularly for LOXL2 [ 160 ]. Despite reaching 90% target engagement, daily treatments are required to ensure complete inhibition due to the high resynthesis rates of lysyl oxidases [ 160 ].…”

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

“…The establishment of target engagement assays has illustrated the dynamic nature of protein resynthesis, particularly for LOXL2 [ 160 ]. Despite reaching 90% target engagement, daily treatments are required to ensure complete inhibition due to the high resynthesis rates of lysyl oxidases [ 160 ]. Presently, in terms of treatment, it is still unclear the role redundancy will play within the lysyl oxidase family, but this will only be a consideration when not utilizing pan-lysyl oxidase inhibitors (e.g., PAT-1251 a LOXL2 inhibitor and PXS-5382 a dual LOXL2/LOXL3 inhibitor).…”

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

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Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

Perryman

Gray

2022

Cancers

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Immunotherapies (such as checkpoint inhibitors) and standard chemotherapies (such as cisplatin) have limitations in the successful treatment of malignant pleural mesothelioma (MPM). Fibrosis is the accumulation of collagen in the extracellular matrix (ECM) of tissues, making them denser than that of healthy tissues and thereby affecting drug delivery and immune cell infiltration. Moreover, fibrosis severely affects the patient’s breathing and quality of life. The production of collagen and its assembly is highly regulated by various enzymes such as lysyl oxidases. Many solid tumors aberrantly express the family of lysyl oxidases (LOX/LOXL). This review examines how LOX/LOXLs were found to be dysregulated in noncancerous and cancerous settings, discusses their roles in solid tumor fibrosis and pathogenesis and explores the role of fibrosis in the development and poor clinical outcomes of patients with MPM. We examine the current preclinical status of drugs targeting LOX/LOXLs and how the incorporation of such drugs may have therapeutic benefits in the treatment and management of patients with MPM.

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Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

Section: Inhibitors Of Lysyl Oxidasesmentioning

confidence: 99%

See 3 more Smart Citations

Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

Perryman

Gray

2022

Cancers

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Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging

et al. 2023

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The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure‐activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.

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