PXS-5120A

Biological Activity

PXS-5120A is a potent, irreversible fluoroallylamine inhibitor of Lysyl Oxidase-like 2/3 (LOXL2/3) with anti-fibrotic activity. PXS-5120A is >300-fold selective for LOXL2 (Ki of 83 nM; pIC50 of 8.4) over LOXL (pIC50 of 5.8)[1]. PXS-5120A (Compound 12k) is a potent inhibitor of the LOXL2/3 enzyme and a moderate blocker of LOXL4. PXS-5120A inhibits recombinant human LOXL2, human fibroblast LOXL2, recombinant mouse LOXL2, recombinant rat LOXL2, collagen oxidation assay, recombinant human LOXL3 and recombinant human LOXL4 with IC50s of 5 nM, 9 nM, 6 nM, 6 nM, 13 nM, 16 nM and 280 nM, respectively. PXS-5129A is readily absorbed following oral gavage, and once in the circulation, rapidly hydrolyzed to release PXS-5120 (free base) in vivo, affording plasma concentrations well above the LOXL2 IC50 (6 nM) for a prolonged period (>6 h) in mice, while remaining well below the IC50 for LOX throughout[1].

References

[1]. Identification and Optimization of Findlay AD, et al. Mechanism-Based Fluoroallylamine Inhibitors of Lysyl Oxidase-like 2/3. J Med Chem. 2019 Nov 14;62(21):9874-9889.