Targeted Polypharmacology: Discovery of a Highly Potent Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-10/-13 Inhibitor.

J Med Chem

Institute of Chemistry and Biotechnology, Center for Organic and Medicinal Chemistry, ZHAW Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.

Published: December 2017

Matrix metalloproteinases (MMPs) play a key role in many diseases like cancer, atherosclerosis or arthritis. Interest in MMP inhibition has been revitalized very recently as the knowledge on the underlying network of biological pathways is steadily growing. On the basis of this new insight into the relevance of MMP-10 and MMP-13 within the MMP network and the ban of hydroxamate inhibitors from clinical development, the discovery of non-hydroxamate multitarget drugs against specific MMPs is of foremost interest. Here, we disclose the discovery of a very potent and selective non-hydroxamate MMP-10/-13 inhibitor. The high potency (IC of 31 nM [MMP-10] and 5 nM [MMP-13]) and selectivity over MMP-1, -2, -3, -7, -8, -9, -12, and -14 enable this compound to decipher disease causing MMP networks and to generate new treatment options through targeted polypharmacology.

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.7b01001DOI Listing

Publication Analysis

Top Keywords

targeted polypharmacology
8
mmp-10/-13 inhibitor
8
polypharmacology discovery
4
discovery highly
4
highly potent
4
potent non-hydroxamate
4
non-hydroxamate dual
4
dual matrix
4
matrix metalloproteinase
4
metalloproteinase mmp-10/-13
4

Similar Publications

Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines.

View Article and Find Full Text PDF

Target cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors; 5-([2,5-Dihydroxybenzyl]amino)salicylamides (Compounds 1-11) were examined for potential anticancer activity, with a trial to assess the underlying possible mechanisms. Compounds were assessed at a single dose against 60 cancer cell lines panel and those with the highest activity were tested in the five-dose assay. COMPARE analysis was conducted to explore potential mechanisms underlying their biological activity.

View Article and Find Full Text PDF

New Promising Steroidal Aromatase Inhibitors with Multi-Target Action on Estrogen and Androgen Receptors for Breast Cancer Treatment.

Cancers (Basel)

January 2025

UCIBIO-Applied Molecular Biosciences Unit, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, n° 228, 4050-313 Porto, Portugal.

Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer-the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment.

View Article and Find Full Text PDF

Glioblastoma is one of the most aggressive brain cancers, characterized by active infiltrative growth and high resistance to radiotherapy and chemotherapy. Sesquiterpene triterpenoids (STLs) and their semi-synthetic analogs are considered as a promising source of novel anti-tumor agents due to their low systemic toxicity and multi-target pharmacological effects on key processes associated with tumor progression. The current review aims to systematize the knowledge on the anti-glioblastoma potential of STLs accumulated over the last decade and to identify key processes in glioblastoma cells that are most susceptible to the action of STLs.

View Article and Find Full Text PDF

The clinical effectiveness of colistin against multidrug-resistant Gram-negative pathogen infections has been threatened by the emergence of the plasmid-mediated colistin-resistant gene mcr-1. This development underscores the urgent need for innovative therapeutic strategies that target resistance mechanisms. In this study, we demonstrated that glabridin can restore the sensitivity of colistin to mcr-1-positive Escherichia coli (E.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!