Abstract
Hodgkin's lymphoma (HL) is the most common malignant lymphoma in young adults in the western world. This disease is characterized by an overexpression of ADAM-10 with increased release of NKG2D ligands, involved in an impaired immune response against tumor cells. We designed and synthesized two new ADAM-10 selective inhibitors, 2 and 3 based on previously published ADAM-17 selective inhibitor 1. The most promising compound was the thiazolidine derivative 3, with nanomolar activity for ADAM-10, high selectivity over ADAM-17 and MMPs and good efficacy in reducing the shedding of NKG2D ligands (MIC-B and ULBP3) in three different HL cell lines at non-toxic doses. Molecular modeling studies were used to drive the design and X-ray crystallography studies were carried out to explain the selectivity of 3 for ADAM-10 over MMPs.
Keywords:
ADAM-10 inhibitors; Hodgkin's lymphoma; NKG2D-L; Sulfonamido-based hydroxamates.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM Proteins / metabolism
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ADAM10 Protein
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Discovery*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Hodgkin Disease / drug therapy*
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Hodgkin Disease / enzymology
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Hodgkin Disease / metabolism*
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Hodgkin Disease / pathology
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Humans
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Ligands
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / metabolism
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Models, Molecular
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Molecular Structure
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NK Cell Lectin-Like Receptor Subfamily K / metabolism*
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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KLRK1 protein, human
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Ligands
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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ADAM10 protein, human