Neddylation is a post-translational modification that conjugates the NEDD8 protein to protein substrates, such as the cullins, which once neddylated join complex to form cullin-RING ubiquitin E3 ligases (CRLs), which in turn play a crucial role in regulating proteasomal degradation. The University of Kentucky has presented preclinical data on their neddylation inhibitor TK-59 as a cancer therapeutic.
Heart failure with preserved ejection fraction (HFpEF) is a disease in which the left ventricle (LV) of the heart shows impaired relaxation during cardiac diastole, often accompanied by structural and functional abnormalities.
Sepsis-induced coagulopathy (SIC) is a complication of sepsis tied to high mortality in patients. Anticoagulation using a coagulation factor IIa and Xa dual inhibitor might have the potential to improve the treatment of this severe condition.
The I148M mutation in the PNPLA3 gene, which encodes patatin-like phospholipase domain-containing protein 3, is known to confer risk of fatty liver, cirrhosis and hepatic inflammation, which may lead to hepatocellular carcinoma or metabolic dysfunction-associated steatohepatitis (MASH).
Using its proprietary FBDD platform, Blacksmith discovered FG-2101, the prodrug form of FG-960, the first known non-hydroxamate LpxC inhibitor that exerted activity against LpxC at the nanomolar range.
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is an attractive therapeutic target due to its involvement in cancer and neurodegenerative diseases. Researchers from the National Health Research Institutes and their collaborators have presented a series of DYRK1A inhibitors for reducing neurofibrillary tangle formation in Alzheimer’s disease.
Growing evidence exists on regulation of the chloride importer solute carrier family 12 member 2 (SLC12A2), also known as NKCC1, as a therapeutic approach to treat neurological disorders. Altered expression of NKCC1 leads to impaired intracellular chloride levels in neurons and imbalance in the excitatory-inhibitory axis in the brain.
COVID-19 has continued to alarm public health, and although several therapeutics and vaccines have been developed, the development of effective vaccines or antibodies is challenging due to mutations in the surface of the spike protein in the SARS-CoV-2 virus.
Pannexin 1 (PANX1) forms channels that may release signaling metabolites that are involved in a variety of pathophysiological processes, such as asthma, diabetes, hypertension or inflammatory bowel disease (IBD), among others. Inhibition of PANX1 when dysregulated has been proposed as a therapeutic approach in the treatment of IBD.
Cannabinoid CB1 receptors have been a potential target for nonopioid-based pain treatment, but actually targeting the pathway has been hindered by issues with tolerance and unwanted CNS side effects. Peripherally selective CB1 agonists developed to overcome these problems have not fully resolved these issues, meaning the peripheral selectivity has to be substantially enhanced.