Rationalized Computer-Aided Design of Matrix-Metalloprotease-Selective Prodrugs

J Med Chem. 2017 May 25;60(10):4496-4502. doi: 10.1021/acs.jmedchem.6b01472.

Mohit Jain ¹, J Jonathan Harburn ¹, Jason H Gill ¹, Paul M Loadman ², Robert A Falconer ², Caitlin A Mooney ³, Steven L Cobb ³, David J Berry ¹

Affiliations

1 School of Medicine, Pharmacy and Health, Durham University , Queen's Campus, Stockton on Tees, TS17 6BH, U.K.
2 Institute of Cancer Therapeutics, ICT Building, University of Bradford , Bradford, BD7 1DP, U.K.
3 Department of Chemistry, Durham University , Lower Mountjoy, South Road, Durham, DH1 3LE, U.K.

PMID: 28471664 DOI: 10.1021/acs.jmedchem.6b01472

Abstract

Matrix Metalloproteinases (MMPs) are central to Cancer development and metastasis. They are highly active in the tumor environment and absent or inactive in normal tissues; therefore they represent viable targets for Cancer drug discovery. In this study we evaluated in silico docking to develop MMP-subtype-selective tumor-activated prodrugs. Proof of principle for this therapeutic approach was demonstrated in vitro against an aggressive human glioma model, with involvement of MMPs confirmed using pharmacological inhibition.

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