The ADAM metalloproteinases.

This review focuses on the role of ADAM-17 in disease. Since its debut as the tumor necrosis factor converting enzyme (TACE), ADAM-17 has been reported to be an indispensible regulator of almost every cellular event from proliferation to migration. The central role of ADAM-17 in cell regulation is rooted in its diverse array of substrates: cytokines, growth factors, and their receptors as well as adhesion molecules are activated or inactivated by their cleavage with ADAM-17. It is therefore not surprising that ADAM-17 is implicated in numerous human diseases including cancer, heart disease, diabetes, rheumatoid arthritis, kidney fibrosis, Alzheimer's disease, and is a promising target for future treatments. The specific role of ADAM-17 in the pathophysiology of these diseases is very complex and depends on the cellular context. To exploit the therapeutic potential of ADAM-17, it is important to understand how its activity is regulated and how specific organs and cells can be targeted to inactivate or activate the enzyme.

ADAM-17: the enzyme that does it all.

As a metalloproteinase specialized in releasing membrane-tethered proteins, A Disintegrin and A Metalloproteinase 17 (ADAM17), also known as Tumor necrosis factor-￻ Converting Enzyme (TACE) or less commonly CD156q, has received more than its share of attention. This is mainly because major contemporary pathologies like cancer, inflammatory and vascular diseases seem to be connected to its cleavage abilities. The involvement in such a broad spectrum of diseases is due to the large variety of substrates that ADAM17 is able to cut. ADAM17 can activate growth factors or inactivate receptors by shedding their extracellular domain from the cell membrane. Similarly, it can detach cells by cleaving cell adhesion molecules. Some of these proteolytic events are part of cleavage cascades known as Regulated Intramembrane Proteolysis and lead to intracellular signaling. It is therefore clear that ADAM17 literally fulfills a key role in diverse processes and pathologies, making it a prime target for developing therapies. Here we review the role of ADAM17 in health and disease and highlight the problems to overcome for ADAM17 to mature towards a therapeutically valuable target.

/pdf/adam17-as-a-therapeutic-target-in-multiple-diseases-w756n6ufze.pdf

ADAM17 as a Therapeutic Target in Multiple Diseases

Recognizing substructures and their relations embedded in a molecular structure representation is a key process for structure-activity or structure-property relationship (SAR/SPR) studies. A molecular structure can be explicitly represented as either a connection table (CT) or linear notation, such as SMILES, which is a language describing the connectivity of atoms in the molecular structure. Conventional SAR/SPR approaches rely on partitioning the CT into a set of predefined substructures as structural descriptors. In this work, we propose a new method to identifying SAR/SPR through linear notation (for example, SMILES) syntax analysis with self-attention mechanism, an interpretable deep learning architecture. The method has been evaluated by predicting chemical properties, toxicology, and bioactivity from experimental data sets. Our results demonstrate that the method yields superior performance compared with state-of-the-art models. Moreover, the method can produce chemically interpretable results, which can be used for a chemist to design and synthesize the activity- or property-improved compounds.

Identifying Structure-Property Relationships through SMILES Syntax Analysis With Self-Attention Mechanism

Current perspective of TACE inhibitors: a review.

Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-alpha production in human whole blood.

Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket.

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Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-alpha production in human whole blood.

Structure-based design of TACE selective inhibitors: manipulations in the S1'-S3' pocket.