Fibrosis plays a major role in the development of metastases and primary tumour growth. A fibrotic microenvironment is required to facilitate colonialization of cancer cells and formation of metastases; while a strong fibrotic stroma can encapsulate a primary tumour limiting the access of therapeutics and immune cells. Fibrosis is the product of excessive collagen and elastin secretion and the subsequent oxidation of lysine or hydroxylysine side chains by lysyl oxidases. These oxidation products can di- or tri-merise to form immature or mature cross-links, respectively. Consequently, the inhibition of lysyl oxidase activity should result in more soluble collagen, which can be easily degraded, providing therapeutic benefits for the treatment of highly fibrotic stroma as well as metastases.
Here, the development of a pan-lysyl oxidase inhibitor is described which has anti-fibrotic properties and reduces primary and secondary tumour size in a model of pancreatic cancer.
PXS-LOX_2 is a small molecule mechanism-based inhibitor of all 5 members of the lysyl oxidase family. It has excellent drug-like properties, very good exposure after oral dosing and successfully completed toxicity tests. Upon a single oral dose, PXS-LOX_2 reduces the lysyl oxidase activity in tissues in a dose dependent manner. Inhibition of enzymatic activity outlasts the exposure in the plasma, as expected for mechanism-based inhibitor. PXS-LOX_2 shows anti-fibrotic activity in standard animal models of fibrosis, unilateral ureter obstruction and bleomycin-induced lung fibrosis.
In a mouse model of orthotopic injection of human pancreatic cancer cells (MiaPaca-2), PXS-LOX_2 reduces the size of the primary and secondary tumour in the presence of standard (gemcitabine, abraxane) therapy.
Based on the pre-clinical data PXS-LOX_2 will enter Phase 1 trials.