Lysyl oxidase-like 2 (LOXL2) is a secreted enzyme that catalyzes the formation of cross-linking in extracellular matrix proteins (collagen and elastin). There are five members of the human LOX protein family, designated LOX and LOX-like 1-4 (LOXL1-4). The expression pattern of LOX family members can alter depending on cell type, differentiation status, development status, and disease status. In addition, the LOX family plays a key role in the cross-linking of elastin and collagen fibrils through elastic oxidation. Besides, LOXL2 is a biomarker of the progress of various diseases, such as liver and lung fibrosis, scleroderma and cancer. Meanwhile, LOXL3 is a new therapeutic target for pulmonary fibrosis. LOXL2 mRNA and protein levels were up-regulated in fibrotic tissues and various solid tumors compared with normal human tissues. The selective inhibition of LOXL2 provides an obvious advantage for its long-term treatment. PXS-5120A is a potent inhibitor of Lysyl oxidase-like 2/3.

PXS-5120A is a potent and irreversible fluoroallylamine inhibitor of Lysyl oxidase-like 2/3. Furthermore, PXS-5120A is in a pro-drug form (PXS-5129A) with anti-fibrotic activity. Meanwhile, PXS-5120A is >300-fold selective for LOXL2 over LOX. PXS-5120A exhibited good selectivity over the related amine oxidase enzymes and showed limited auxiliary pharmacology in standard profiling assays. Furthermore, PXS-5120A is metabolically stable in vitro and has moderate protein plasma binding. In addition, PXS-5120A is a potent inhibitor of the LOXL3 enzyme and a moderate blocker of LOXL4. PXS-5120A is important for both liver and lung diseases and affords a dual inhibitor with an increased chance of reducing fibrosis in disease states. All in all, PXS-5120A is a potent and irreversible fluoroallylamine inhibitor of Lysyl oxidase-like 2/3 with anti-fibrotic activity.



Findlay AD, et al. J Med Chem. 2019 Nov 14;62(21):9874-9889.