Researchers at China Pharmaceutical University and Chongqing Innovation Institute, China Pharmaceutical University have divulged ubiquitin C-terminal hydrolase 7 (USP7; HAUSP) inhibitors reported to be useful for the treatment of inflammatory disorders, infections and cancer.
Positive allosteric modulators (PAMs) of the muscarinic acetylcholine M4 receptor show potential against schizophrenia because they can enhance endogenous acetylcholine signaling, which in turn may mitigate psychotic symptoms as well as improve attention and working memory in individuals with the disorder. However, the efficacy of a promising PAM, CVL-231, has been disappointing in clinical trials.
The enzyme PARP1 helps repair single-stranded DNA breaks, and its inhibition shows antitumor efficacy in ovarian, breast, prostate and pancreatic cancers involving mutations in BRCA1 or BRCA2. However, resistance to PARP1 inhibition is a major problem.
Excessive signaling by platelet-derived growth factor receptor (PDGFR)-α, a transmembrane tyrosine kinase, helps drive the rapid angiogenesis that many types of tumor cells need in order to proliferate and metastasize.
In cancer, Cdc37 is phosphorylated by casein kinase 2 (CK2) and then the phosphoprotein binds to various kinase ‘clients’ and to the chaperone Hsp90. Hsp90 facilitates the folding of the clients into fully active forms to drive the cell cycle. The plant-derived quinine methid triterpenoid celastrol can inhibit the interaction between Hsp90 and Cdc37 and thereby slow cancer growth by arresting the cell cycle and inducing apoptosis. However, researchers at China Pharmaceutical University China wanted to inhibit the ‘Hsp90-Cdc37-kinase’ cycle at multiple points simultaneously for greater therapeutic effect.
China Pharmaceutical University has patented non-ubiquitin proteolysis targeting chimera (NuTACs) comprising proteasomal ubiquitin receptor ADRM1 (ARM1; hRpn13) linked to programmed cell death 1 ligand 1 (CD274; PD-L1) and/or bromodomain-containing protein 4 (BRD4; HUNK1)-targeting moiety. They are reported to be useful for the treatment of cancer, eye disorders, viral infections, autoimmune diseases, inflammatory disorders and systemic inflammatory response syndrome.
Researchers from China Pharmaceutical University and collaborators have identified various naphthalene and indane derivatives as selective USP7 inhibitors.
A hallmark of liver fibrosis is the differentiation of hepatic stellate cells (HSCs) into myofibroblast-like cells, which are responsible for excessive extracellular matrix deposition. Among the key mediators of HSC activation, transforming growth factor-beta 1 (TGF-β1) is considered the most potent pro-fibrotic cytokine.
Scientists at Ascentage Pharma (Suzhou) Co. Ltd. and China Pharmaceutical University have synthesized molecular glue degrader compounds acting as eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1)/CRBN interaction inducers for GSPT1 degradation reported to be useful for the treatment of cancer, viral infections, aging, immunological disorders and neurological disorders.
