Regulation of protein phosphorylation by PTPN2 and its small-molecule inhibitors/degraders as a potential disease treatment strategy.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is an enzyme that dephosphorylates proteins with tyrosine residues, thereby modulating relevant signaling pathways in vivo. PTPN2 acts as tumor suppressor or tumor promoter depending on the context. In some cancers, such as colorectal, and lung cancer, PTPN2 defects could impair the protein tyrosine kinase pathway, which is often over-activated in cancer cells, and inhibit tumor development and progression. However, PTPN2 can also suppress tumor immunity by regulating immune cells and cytokines. The structure, functions, and substrates of PTPN2 in various tumor cells were reviewed in this paper. And we summarized the research status of small molecule inhibitors and degraders of PTPN2. It also highlights the potential opportunities and challenges for developing PTPN2 inhibitors as anticancer drugs.

Expanding role of CXCR2 and therapeutic potential of CXCR2 antagonists in inflammatory diseases and cancers.

C-X-C motif chemokine receptor 2 (CXCR2) is G protein-coupled receptor (GPCR) and plays important roles in various inflammatory diseases and cancers, including chronic obstructive pulmonary disease (COPD), atherosclerosis, asthma, and pancreatic cancer. Upregulation of CXCR2 is closely associated with the migration of neutrophils and monocytes. To date, many small-molecule CXCR2 antagonists have entered clinical trials, showing favorable safety and therapeutic effects. Hence, we provide an overview containing the discovery history, protein structure, signaling pathways, biological functions, structure-activity relationships and clinical significance of CXCR2 antagonists in inflammatory diseases and cancers. According to the latest development and recent clinical progress of CXCR2 small molecule antagonists, we speculated that CXCR2 can be used as a biomarker and a new target for diabetes and that CXCR2 antagonists may also attenuate lung injury in coronavirus disease 2019 (COVID-19).

Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives to reduce SREBPs expression for the treatment of hyperlipidemia.

Statins play an important role in the treatment of hyperlipidemia, but drug resistance and adverse effects greatly limits their application. To discover new lipid-lowering drugs, three different series of tetrahydroprotoberberine derivatives (THPBs) were designed and synthesized. These compounds were first tested for their effects on viability of HepG2 cells and 21 compounds with the percent of cell viability over 90% were further screened to evaluate their ability to reduce total cholesterol (TC) and triglyceride (TG) levels. Among these derivatives, two compounds displayed significant down-regulation both intracellular of TC and TG content, especially compound 49 exhibited the greatest efficacy. Mechanistically, compound 49 promoted proteasomal degradation of SREBPs. Importantly, compound 49 displayed superior bioavailability (F = 65.1%) and obvious efficacy in the treatment of high fat diet induced obesity in vivo. Therefore, compound 49 is a promising candidate to develop new treatment of hyperlipidemia.