LOXL2 Inhibitors and Breast Cancer Progression

Abstract

LOX (lysyl oxidase) and lysyl oxidase like-1-4 (LOXL 1-4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic approach for breast cancer treatment.

Keywords: BAPN; EMT; breast cancer; cell invasion; inhibitors; lysyl-oxidase; lysyl-oxidase like 2; metastases.

Figure 1

Chemical structure of β-aminopropionitrile (BAPN).

Figure 2

Structure of LOX proteins. (A) Crystal structure of human LOXL2 in a precursor state obtained by Zhang et al. (2018) [9]. The SRCR domains 3 and 4 are colored in red and orange, respectively; the catalytic domain is colored in blue. The glycosyl groups at Asn-644 are shown. Zinc and calcium ions are represented as purple, blue and green spheres, respectively. Image was prepared with PDB (PDBID 5ZE3) [10]. (B) Schematic representation of the structure and homology of human LOX isoenzymes. Due to similarities in the domain arrangement, LOX and LOXL1 represent one LOX subfamily, whereas LOXL2-4 constitute another LOX subfamily.

Figure 3

Lysine tyrosylquinone (LTQ).

Figure 4

Intracellular and extracellular pathways involving LOXL2 in cancer metastasis-related processes. Akt, protein kinase B; EMT, epithelial–mesenchymal transition; FAK, focal adhesion kinase; Pl3k, phosphoinositide 3-kinases; SNAIL, zinc finger protein; Src, proto-oncogene tyrosine-protein kinase Src. Adapted from [31,32].

Figure 5

Structures of PXS-5153A; PAT-1251; CCT365623; an aminomethylenethiophene (AMT), 5-(naphthalen-2-ylsulfonyl)thiophen-2-yl)methamine 1; and a 2-aminomethylene-5-sulponylthiazole (AMTz), (5-(naphthalen-2-ylsulfonyl)thiazol-2-yl)methanamine 2.