The design and synthesis of selective ADAM17 inhibitors
2017
Hochschulschrift
Zugriff:
ADAM 17 is a key enzyme in the regulation of a number of downstream pathways in inflammation and cell adhesion. ADAM17 dysregulation has been noted in a number of cancer types, leading to an increased invasive phenotype. Previous attempts at targeting ADAM 17 in the clinic have failed due to low efficacy and off-target effects such as liver toxicity and musculo-skeletal defects, these have been linked to targeting other MMPs concurrently. We developed a number of novel scaffolds to probe the SAR of the active site of ADAM17, and glean knowledge from this to inform further drug design choices and to develop a cleanly selective and drug-like candidate. We used the enzymes MMP-2 and 9 as indicators of selectivity due to the high structural homology of the active site in comparison to ADAM17. Another facet of this work was the discovery and follow up of a number of highly active and selective MMP-2 inhibitors. MMP-2 is a valuable tumorigenic target, a well-known link in increasing the metastatic phenotype of multiple cancers through its role in cell matrix degradation. In a similar fashion, iterative SAR was used to inform our scaffold improvement, whilst also trying to improve the drug-like properties of our compounds. This work has sought to develop single target selective inhibitors against both ADAM17 and MMP-2. Beginning with fragment scaffolds, these were further decorated with more functional groups through rounds of SAR targeting different regions of the enzymes active site, to engender selectivity. This has led to development of a number of highly biologically active and selective inhibitors against ADAM 17 and MMP-2.
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The design and synthesis of selective ADAM17 inhibitors
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Autor/in / Beteiligte Person: | Gilliland, Peter |
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Veröffentlichung: | 2017 |
Medientyp: | Hochschulschrift |
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