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Published on: May 22, 2019
Enriching the Arsenal of Pharmacological Tools against MICAL2
Ivana Barravecchia1,2, Elisabetta Barresi2, Camilla Russo3
1Institute of Life Sciences, Scuola Superiore Sant'Anna, Via G. Moruzzi 1, 56124 Pisa, Italy.
Abstract:
Molecule interacting with CasL 2 (MICAL2), a cytoskeleton dynamics regulator, are strongly expressed in several human cancer types, especially at the invasive front, in metastasizing cancer cells and in the neo-angiogenic vasculature. Although a plethora of data exist and stress a growing relevance of MICAL2 to human cancer, it is worth noting that only one small-molecule inhibitor, named CCG-1423 (1), is known to date. Herein, with the aim to develop novel MICAL2 inhibitors, starting from CCG-1423 (1), a small library of new compounds was synthetized and biologically evaluated on human dermal microvascular endothelial cells (HMEC-1) and on renal cell adenocarcinoma (786-O) cells. Among the novel compounds, 10 and 7 gave interesting results in terms of reduction in cell proliferation and/or motility, whereas no effects were observed in MICAL2-knocked down cells. Aside from the interesting biological activities, this work provides the first structure-activity relationships (SARs) of CCG-1423 (1), thus providing precious information for the discovery of new MICAL2 inhibitors.
Insights
Researchers developed new MICAL2 inhibitors to combat cancer. Compounds 10 and 7 reduced cancer cell proliferation and motility, offering new avenues for MICAL2-targeted cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Molecule interacting with CasL 2 (MICAL2) regulates cytoskeleton dynamics and is highly expressed in various human cancers, particularly at invasive fronts and in metastatic cells.
- MICAL2's role in cancer progression is increasingly recognized, yet only one small-molecule inhibitor, CCG-1423, is currently known.
Purpose of the Study:
- To synthesize and evaluate novel MICAL2 inhibitors based on the CCG-1423 scaffold.
- To establish the first structure-activity relationships (SARs) for CCG-1423 derivatives to guide future drug discovery.
Main Methods:
- Synthesis of a small library of novel compounds derived from CCG-1423.
- Biological evaluation of synthesized compounds on human dermal microvascular endothelial cells (HMEC-1) and renal cell adenocarcinoma (786-O) cells.
- Assessment of compound effects on cell proliferation and motility, including experiments with MICAL2-knocked down cells.
Main Results:
- Novel compounds 10 and 7 demonstrated significant reduction in cancer cell proliferation and/or motility.
- The observed biological activities were dependent on MICAL2 expression, as no effects were seen in MICAL2-knocked down cells.
- The study established the initial structure-activity relationships (SARs) for CCG-1423 analogs.
Conclusions:
- Compounds 10 and 7 show promise as potential MICAL2-targeting agents for cancer therapy.
- The established SARs provide a foundation for designing more potent and selective MICAL2 inhibitors.
- This research contributes valuable insights into the development of novel therapeutic strategies for MICAL2-associated cancers.
