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

• Published in: Journal of medicinal chemistry Vol. 60; no. 23; pp. 9585 - 9598
• Main Authors: Senn, Nicole, Ott, Michael, Lanz, Jan, Riedl, Rainer
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2017; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Drug Design; Humans; Life Sciences & Biomedicine; Matrix Metalloproteinase 10 - metabolism; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors - pharmacology; Models, Molecular; Pharmacology & Pharmacy; Polypharmacology; Science & Technology; Structure-Activity Relationship; ACTIVATION; PHARMACOLOGY; MATRIX-METALLOPROTEINASE-10; MMP-10; SELECTIVITY; HOPE; PROCOLLAGENASE; STRUCTURE-BASED DESIGN
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01001

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 (IC50 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.