Related Experiment Video
Updated: May 29, 2026
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
From Virtual Screening to Cell Phenotype: 4-Thiazolidone Scaffolds Targeting LOXL2 in Breast Cancer
Sandra Ferreira1,2, Beatriz Santos1, Matilde Tavares1
1CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Lisbon, Portugal.
Abstract:
Lysyl Oxidases (LOXs) catalyse elastin and collagen cross-linking in the extracellular matrix and have been implicated in cancer cell progression and metastases, particularly in breast cancer. In this study, we sought small-molecule inhibitors of LOXL2 using a library of 4-thiazolidones supported by molecular docking. Five candidates were prioritised, with Les 5740 displaying the highest LOXL2 inhibitory activity (IC50 of 27 μM). Although Les 5740 showed low cytotoxicity in various cancer and normal-like cell lines, the triple-negative breast cancer (TNBC) cell line MDA-MB-231 showed increased susceptibility to this molecule. Les 5740 did not induce DNA damage in mammary cells. At 30 μM, it increased TNBC cells' necrosis. The impact of a non-toxic concentration of Les 5740 (5 μM) on TNBC cell motility was evaluated. Les 5740 reduced 2D chemoinvasion and altered cell morphology. These findings are consistent with a potential reduction in extracellular matrix stiffness as a consequence of LOXL2 inhibition. Les 5740 mildly inhibited tubulin polymerisation, supporting a multi-target profile. Overall, Les 5740 should be viewed as a starting scaffold with LOXL2 inhibitory activity and broader cellular effects, motivating optimisation toward more potent and selective LOXL2 inhibitors for breast cancer therapy.
Insights
A novel compound, Les 5740, inhibits lysyl oxidase-like 2 (LOXL2), an enzyme involved in breast cancer progression. This inhibitor shows potential for reducing triple-negative breast cancer cell invasion and motility.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Lysyl oxidases (LOXs) are crucial for extracellular matrix cross-linking.
- LOX enzymes, particularly LOXL2, are implicated in cancer progression and metastasis, especially in breast cancer.
Purpose of the Study:
- To identify small-molecule inhibitors of LOXL2 using a 4-thiazolidone library.
- To evaluate the efficacy and cellular effects of identified inhibitors on breast cancer cells.
Main Methods:
- Molecular docking was employed to screen a library of 4-thiazolidones.
- In vitro assays were used to determine LOXL2 inhibitory activity (IC50) and cytotoxicity.
- Cellular assays assessed effects on necrosis, DNA damage, cell motility, chemoinvasion, and tubulin polymerization.
Main Results:
- Les 5740 demonstrated significant LOXL2 inhibitory activity (IC50 = 27 μM) with low cytotoxicity.
- Les 5740 increased necrosis in triple-negative breast cancer (TNBC) cells (MDA-MB-231) at 30 μM.
- At a non-toxic concentration (5 μM), Les 5740 reduced TNBC cell chemoinvasion and altered cell morphology, suggesting reduced extracellular matrix stiffness.
Conclusions:
- Les 5740 is a promising starting scaffold for developing LOXL2 inhibitors.
- The compound exhibits broader cellular effects, including mild inhibition of tubulin polymerization.
- Further optimization of Les 5740 is warranted for potent and selective breast cancer therapeutics targeting LOXL2.