Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure–Activity Relationships

Leung, Leo; Niculescu‐Duvaz, Dan; Smithen, Deborah A.; Lopes, Filipa; Callens, Cedric; McLeary, Robert; Saturno, Grazia; Davies, Lawrence; Aljarah, Mohammed; Brown, Michael; Johnson, Linda Y; Zambon, Alfonso; Chambers, Tim; Ménard, Delphine; Bayliss, Natasha; Knight, Ruth; Fish, Laura J.; Lawrence, Rae; Challinor, Mairi; Tang, Haoran; Marais, Richard; Springer, Caroline J.

doi:10.1021/acs.jmedchem.9b00335

Cited by 41 publications

(65 citation statements)

References 24 publications

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“…Although BAPN is the most commonly used LOX inhibitor, it inhibits all LOX family members. In this line, there have been several recent efforts to identify novel and selective small molecule inhibitors against different family members, including LOX 66 and LOXL2 67 that can hopefully be tested in clinics to improve patient outcome in aggressive cancers, including the chemoresistant TNBCs. Moreover, our in vitro and in vivo data showing strong chemosensitization upon inhibiting FAK or Src kinases suggest that FAK/Src axis is critical for tumor cell survival in the presence of chemotherapy and targeting these proteins could also be an effective strategy to overcome chemoresistance in TNBCs in the future.…”

Section: Discussionmentioning

confidence: 99%

Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer

et al. 2020

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Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxiarepressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer

et al. 2020

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“…In vivo pharmacokinetics tests were conducted on the example compound from Entry 3 (Table ), recently revealed as CCT365623, using a mouse model dosed at 10 mg kg −1 intravenously and 50 mg kg −1 orally . A rat was also dosed at 4 mg mg −1 intravenously and 20 mg kg −1 orally .…”

Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

“…Recently the medicinal chemistry campaign that delivered CCT365623 from a high‐throughput screen has been disclosed . In particular, the key aminomethylenethiophene (AMT) moeity proved a potent LOX inhibitor scaffold but with a poor pharmacokinetic profile.…”

Section: Modulation Of Loxl2 Activitymentioning

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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Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure–Activity Relationships

Cited by 41 publications

References 24 publications

Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer

Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast 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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