Challenge: PROTACs (PROteolysis TArgeting Chimeras) are bifunctional drugs that recruit a ubiquitin E3 ligase to a targeted protein, thereby catalyzing poly-ubiquitylation of the target and its subsequent degradation by the proteasome. PROTAC induced protein degradation offers advantages over classical enzyme inhibition: it acts via a catalytic instead of occupancy-based mechanism and shows superior efficacy with…
Challenge: G-protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and represent an important class of targets that could be modulated by antibody (Ab)-based therapeutics. However, finding function-modifying antibodies against GPCRs remains a challenge due to the difficulty of preparing purified antigens, poor immunogenicity, small extracellular loops and low expression levels on cells.…
Challenge: Poor efficacy and unpredictable toxic effects are leading causes for the removal of drugs from the market. Many drugs act unpredictably in patients because the preclinical studies fail to accurately model human biology. In particular, the liver requires special attention as it is responsible for metabolizing drugs. Thus, improved liver models could identify and…
Challenge: Endoplasmic reticulum (ER) stress occurs when the folding of secreted proteins within the ER lumen is disturbed. The unfolded protein response (UPR) comprises several mechanisms. These adaptive responses attempt to overcome ER protein folding disturbances to promote cellular homeostasis and cell survival. ER stress and the UPR are implicated in many diseases such as…
Challenge: In recent years, only 8% of new oncology drugs have been approved for clinical use. One of the major challenges has been matching an appropriate therapeutic strategy to a cancer indication due to the heterogeneity of the disease. Nevertheless, the personalized medicine approach is not a simple process, as each cancer type represents a…
Challenge: Ion channels are involved in numerous physiological functions, and as drug targets have been implicated in a wide range of pathological conditions. However, despite considerable effort, channel-targeted drug discovery has been hampered by the absence of adequate tools to functionally screen molecules that can modulate channel activity. Solution: The researchers have developed an innovative…
Challenge: With the unique property of nuclear receptors (NRs) to directly interact with genomic DNA and control the expression of genes, nuclear receptors play key roles in both embryonic development and adult homeostasis as well as in many diseases. With a total of 48 different human receptors and 6 epigenetic-regulating cofactors identified, the is still…
Challenge: Membrane proteins, representing approximately one-third of all proteins in a cell, interact with each other and are responsible for a variety of processes, making them attractive therapeutic targets for many diseases such as hypertension, diabetes, neurological disorders and various cancers. In fact, membrane proteins represent 60% of all clinical drug targets, however, they are…
Challenge: Current therapies for heart failure primarily relieve symptoms, but most fail to correct organ dysfunction. New therapies, to target and improve cardiomyocyte function, are challenging to develop because of the complex functions of the heart muscle and the difficulty in modeling heart cell behavior. The same problems underlie the difficulty in assessing the cardiotoxic…
Challenge: G protein-coupled receptors (GPCRs) form the largest family of cell surface receptors involved in signal transduction of many hormones and transmitters. It follows that drugs targeting GPCRs represent close to 40% of all drugs on the market today. Recent discoveries regarding their function and mechanism of action help pave the way for the development…