2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth

Smithen, Deborah A.; Leung, Leo; Challinor, Mairi; Lawrence, Rae; Tang, Haoran; Niculescu‐Duvaz, Dan; Pearce, Simon P.; McLeary, Robert; Lopes, Filipa; Aljarah, Mohammed; Brown, Michael; Johnson, Linda Y; Thomson, Graeme; Marais, Richard; Springer, Caroline J.

doi:10.1021/acs.jmedchem.9b01112

Cited by 31 publications

(34 citation statements)

References 45 publications

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“…Springer et al demonstrated that the LOX inhibitor CCT365623, bearing an aminomethylenethiophene (AMT) scaffold, has exhibited anti-metastasis efficacy in a LOX-driven spontaneous breast cancer model [ 98 ]. The team soon after suggested a series of 2-aminomethylene-5-sulfonylthiazole (AMTz) as dual inhibitors of LOX and LOXL2 [ 99 ]. One of the AMTz-bearing inhibitors, AMTz-21b, effectively suppressed tumor growth in their spontaneous breast cancer mouse model [ 99 ].…”

Section: Therapeutic Potential Of Targeting Approaches On Lox Famimentioning

confidence: 99%

“…The team soon after suggested a series of 2-aminomethylene-5-sulfonylthiazole (AMTz) as dual inhibitors of LOX and LOXL2 [ 99 ]. One of the AMTz-bearing inhibitors, AMTz-21b, effectively suppressed tumor growth in their spontaneous breast cancer mouse model [ 99 ]. Meanwhile, dextran sulfate (DS) acts to down-regulate the expression of LOX to suppress invasive and migratory behaviors in gastric cancer cells [ 100 ].…”

Section: Therapeutic Potential Of Targeting Approaches On Lox Famimentioning

confidence: 99%

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Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

Lin

Yang

et al. 2020

IJMS

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The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.

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Section: Therapeutic Potential Of Targeting Approaches On Lox Famimentioning

confidence: 99%

Section: Therapeutic Potential Of Targeting Approaches On Lox Famimentioning

confidence: 99%

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

Lin

Yang

et al. 2020

IJMS

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“…In summary 21b, coupled with the improved PK profile and LOXL2 selectivity, demonstrated anti-tumor efficacy in a LOX-dependent genetically engineered mouse model (GEMM) breast cancer model. [139] The exemplar compound in Entry 5 (Table 3), was tested in a mouse model. It showed a reduction in cancer tongue volume and metastasis of cancer in oral metastatic cancer within a mice model.…”

Section: Next Generation Small Molecule Inhibitors Of Loxl2mentioning

confidence: 99%

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Lysyl oxidase‐like 2 (LOXL2) is an emerging drug target against metastatic disease owing to its role in the upregulation of key processes including epithelial‐mesenchymal transition (EMT) and invasion. Recent activity in the field of small molecule LOXL2 inhibitor development by pharmaceutical and academic laboratories has renewed interest in targeting LOXL2. Herein, 1) the viability of LOXL2 as a drug target for the treatment of metastatic disease through an investigation of its biological actions is determined; 2) the pitfalls of an antibody approach are considered; and 3) the small molecule approaches emerging in the scientific and patent literature are reviewed. This review identifies that LOXL2 is localized and active intracellularly and extracellularly in invasive cancer cells. LOXL2 has been implicated in a number of established signaling pathways involved in tumor progression, further highlighting its appeal as a target in metastatic disease. Previously, limited chemical inhibitors have been developed; however, their selectivity profile for the LOX family has proven controversial. Antibodies, such as simtuzumab, have been developed selectively against LOXL2. Simtuzumab, in particular, progresses into phase II trials but it was ultimately terminated. The small molecule inhibitors of LOXL2 are summarized, some of which are now in the early stages of clinical trials.

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“…The most established LOXL2 inhibitor is β-aminoproprionitrile (BAPN), which irreversibly inhibits the enzyme activity of LOXL2 (34). Recently, a subseries of LOXL2 specific inhibitors containing an aminomethiophene (AMT) scaffold were revealed to inhibit tumor growth (35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial-mesenchymal transition by reducing E-cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose-1, 6-biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail-dependent manner. Overexpression of the point-mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild-type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2-IN-1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF-1α and VEGF in HCC cells, but not in FBP1-knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF-1α/VEGF signaling pathways via the Snail-FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

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2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth

Cited by 31 publications

References 45 publications

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

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