2. Academic Validation
  3. 2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth

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

  • J Med Chem. 2020 Mar 12;63(5):2308-2324. doi: 10.1021/acs.jmedchem.9b01112.
Deborah A Smithen 1 2,  Leo M H Leung 1 2,  Mairi Challinor 1,  Rae Lawrence 1,  HaoRan Tang 3,  Dan Niculescu-Duvaz 1 2,  Simon P Pearce 4,  Robert Mcleary 1 2,  Filipa Lopes 1 2,  Mohammed Aljarah 1 2,  Michael Brown 1 2,  Louise Johnson 2,  Graeme Thomson 1,  Richard Marais 3,  Caroline Springer 1 2
Affiliations

Affiliations

  • 1 Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
  • 2 Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, London SM2 5NG, United Kingdom.
  • 3 Molecular Oncology Team, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
  • 4 Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
PMID: 31430136 DOI: 10.1021/acs.jmedchem.9b01112
Abstract

The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links 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 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 toward 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 antitumor efficacy, with significantly reduced tumor growth in a spontaneous breast Cancer genetically engineered mouse model.

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