2-Aminomethylene-5-Sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth

Deborah A Smithen, Leo Leung, Mairi Challinor, Rae Lawrence, Haoran Tang, Dan Niculescu-duvaz, Simon P Pearce, Robert Mcleary, Filipa Lopes, Mohammed Aljarah, Michael Brown, Louise Johnson, Graeme Thomson, Richard Marais, Caroline Springer

Research output: Contribution to journalArticlepeer-review


The Lysyl Oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of crosslinks in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease, and have thus become an attractive therapeutic target for many types of invasive cancers. Following on from our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold. Incorporation of a thiazole core leads to improved potency towards LOXL2 inhibition via an irreversible binding mode of inhibition. SAR studies have enabled the discovery of a predictive 3DQSAR model. Lead AMTz inhibitors exhibit improved pharmacokinetic properties and excellent anti-tumor efficacy, with significantly reduced tumor growth in a spontaneous breast cancer genetically engineered mouse model.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Early online date20 Aug 2019
Publication statusE-pub ahead of print - 20 Aug 2019


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