USP7 as an emerging therapeutic target: A key regulator of protein homeostasis.

Maintaining protein balance within a cell is essential for proper cellular function, and disruptions in the ubiquitin-proteasome pathway, which is responsible for degrading and recycling unnecessary or damaged proteins, can lead to various diseases. Deubiquitinating enzymes play a vital role in regulating protein homeostasis by removing ubiquitin chains from substrate proteins, thereby controlling important cellular processes, such as apoptosis and DNA repair. Among these enzymes, ubiquitin-specific protease 7 (USP7) is of particular interest. USP7 is a cysteine protease consisting of a TRAF region, catalytic region, and C-terminal ubiquitin-like (UBL) region, and it interacts with tumor suppressors, transcription factors, and other key proteins involved in cell cycle regulation and epigenetic control. Moreover, USP7 has been implicated in the pathogenesis and progression of various diseases, including cancer, inflammation, neurodegenerative conditions, and viral infections. Overall, characterizing the functions of USP7 is crucial for understanding the pathophysiology of diverse diseases and devising innovative therapeutic strategies. This article reviews the structure and function of USP7 and its complexes, its association with diseases, and its known inhibitors and thus represents a valuable resource for advancing USP7 inhibitor development and promoting potential future treatment options for a wide range of diseases.

Curriculum vitae of HDAC6 in solid tumors.

Histone deacetylase 6 (HDAC6) is the only member of the HDAC family that resides primarily in the cytoplasm with two catalytic domains and a ubiquitin-binding domain. HDAC6 is highly expressed in various solid tumors and participates in a wide range of biological activities, including hormone receptors, the p53 signaling pathway, and the kinase cascade signaling pathway due to its unique structural foundation and abundant substrate types. Additionally, HDAC6 can function as an oncogenic factor in solid tumors, boosting tumor cell proliferation, invasion and metastasis, drug resistance, stemness, and lowering tumor cell immunogenicity, so assisting in carcinogenesis. Pan-HDAC inhibitors for cancer prevention are associated with potential cardiotoxicity in clinical investigations. It's interesting that HDAC6 silencing didn't cause any significant harm to normal cells. Currently, the use of HDAC6 specific inhibitors, individually or in combination, is among the most promising therapies in solid tumors. This review's objective is to give a general overview of the structure, biological functions, and mechanism of HDAC6 in solid tumor cells and in the immunological milieu and discuss the preclinical and clinical trials of selective HDAC6 inhibitors. These endeavors highlight that targeting HDAC6 could effectively kill tumor cells and enhance patients' immunity during solid tumor therapy.

Identification of novel 1,3-diaryl-1,2,4-triazole-capped histone deacetylase 6 inhibitors with potential anti-gastric cancer activity.

Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of many cellular pathways in tumors due to its unique structure basis and abundant substrate types. Over the past few decades, the role played by HDAC6 inhibitors as anticancer agents has sparked great interest of biochemists worldwide. However, they were less reported for gastric cancer therapy. In this paper, with the help of bioisosteric replacement, in-house library screening, and lead optimization strategies, we designed, synthesized and verified a series of 1,3-diaryl-1,2,4-triazole-capped HDAC6 inhibitors with promising anti-gastric cancer activities. Amongst, compound 9r displayed the best inhibitory activity towards HDAC6 (IC50 = 30.6 nM), with 128-fold selectivity over HDAC1. Further BLI and CETSA assay proved the high affinity of 9r to HDAC6. In addition, 9r could dose-dependently upregulate the levels of acetylated α-tubulin, without significant effect on acetylated histone H3 in MGC803 cells. Besides, 9r exhibited potent antiproliferative effect on MGC803 cells, and promoted apoptosis and suppressed the metastasis without obvious toxicity, suggesting 9r would serve as a potential lead compound for the development of novel therapeutic agents of gastric cancer.