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.
Highlights
Molecule interacting with CasL 2 (MICAL2) (Molecule Interacting with CasL 2) is a multidomain nucleocytoplasmic protein belonging to the MICALs family
With the aim to enlarge the arsenal of pharmacological tools to inhibit MICAL2, starting from CCG-1423 molecular structure (1, Figure 1), a small library of diverse analogues was synthetized and biologically evaluated on different MICAL2expressing endothelial cells (ECs) and on cancer cell lines in which MICAL2 gene was knocked down [7]
We previously showed that MICAL2 is a new prometastatic gene, expressed in a variety of solid metastatic human cancer types [7] and it is expressed in ECs of neoangiogenic capillaries irrorating solid tumors and in inflammation-related neoangiogenesis [13]
Summary
MICAL2 (Molecule Interacting with CasL 2) is a multidomain nucleocytoplasmic protein belonging to the MICALs family. In Homo sapiens, this family consists of three members (MICAL1, MICAL2 and MICAL3) and two MICAL-like homologs (MICAL-L1 and MICAL-L2) [1,2,3]. MICAL proteins are redox enzymes that exert a dynamic control over polymerization of actin, one of the most abundant proteins in eukaryotic cells that plays an essential role in basic cell functions ranging from cell shape, adhesion, and motility to proliferation, differentiation, and survival. MICALs are involved in key physiological functions such as cytoskeleton remodeling, vesicle trafficking, axon guidance, autophagy and phagocytosis, and angiogenesis. The structural organization of MICALs clearly reflects some of these functions [1].
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