Publications by authors named "Mohammed Aljarah"

2 Publications

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

J Med Chem 2020 03 4;63(5):2308-2324. Epub 2019 Sep 4.

Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.

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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http://dx.doi.org/10.1021/acs.jmedchem.9b01112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073924PMC
March 2020

Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships.

J Med Chem 2019 06 23;62(12):5863-5884. Epub 2019 May 23.

Cancer Research UK Centre for Cancer Therapeutics , The Institute of Cancer Research , 15 Cotswold Road , London SM2 5NG , United Kingdom.

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High-throughput screening provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half-maximal inhibitory concentrations (IC) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937593PMC
June 2019