Drug Discovery in Liver Disease Using Kinome Profiling

Abstract

The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for untold human misery. As biochemical nexus, with kinases being master regulators of cellular biochemistry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.

Rosa26-LSL-dCas9-VPR: a versatile mouse model for tissue specific and simultaneous activation of multiple genes for drug discovery

“…The liver is one of the most important organs in the body, which is directly or indirectly involved in many essential physiological processes, where reduction or loss of liver function can be life threatening [25][26][27][28][29][30][31][32][33] . Hence, liver associated enzymes, circulating proteins and cell receptors are popular targets in the focus of ongoing drug discovery approaches [21][22][23][24][25][26][27][28] .…”

“…The liver is one of the most important organs in the body, which is directly or indirectly involved in many essential physiological processes, where reduction or loss of liver function can be life threatening [25][26][27][28][29][30][31][32][33] . Hence, liver associated enzymes, circulating proteins and cell receptors are popular targets in the focus of ongoing drug discovery approaches [21][22][23][24][25][26][27][28] . In this context, hepatocyte expressed LDLR plays an important role in plasma cholesterol homeostasis, where dysregulation leads to a higher risk for the development of cardiovascular diseases 29 LDLR is located at the cell surface of hepatocytes, where it interacts with plasma derived LDL.…”

Recent Advances in Kinase Drug Discovery Part I: The Editors’ Take

“… Recent advances in kinase drug discovery span the drug discovery pipeline from target identification through to pharmacovigilance. These advances are illustrated in six primary research articles covering kinome array profiling [ 4 ], structure-guided drug development [ 5 , 6 ], rational computational design [ 7 ], targeting the protein/peptide substrate binding site [ 8 ] and combinatorial drug treatment [ 9 ]; and nine topical reviews on TAO kinases [ 10 ], liver disease [ 11 ], AMPK [ 3 ], pancreatic cancer [ 12 ], urothelial carcinoma [ 13 ], Flaviviridae infections [ 14 ], squamous cell carcinoma [ 15 ], thyroid cancer [ 16 ] and adverse reactions to JAK inhibitors [ 17 ]. The indicated figures from special issue papers have been re-used with permission from the authors.…”

“…Target identification and validation are aided by the application of modern technologies that allow for the monitoring not just of protein levels, but protein activity. Such techniques look set to revolutionise this area, as exemplified in an article by Yu and co-authors [ 11 ], who make the case for the use of kinome profiling to expand and deepen our understanding of kinase activity in healthy compared to diseased liver tissue. They provide a useful summary of two widely applied methodologies; mass spectrometry and array-based techniques.…”