Introduction: Since the first pan-HDAC inhibitor SAHA was approved by U.S. FDA 10 years ago, HDACs including SIRT1-7 have received significant attention due to the fact that aberrant histone deacetylase activtiy has been implicated in a variety of human diseases, such as cancers, virus infection, and neurodegenerative diseases. During the past years, a considerable achievement of development of isoform- or class-selective HDAC inhibitors has been made, yielding many drug candidates for further clinical studies, which represents a state-of-the-art technology in the drug discovery arena. Areas covered: This review covers new patents and articles about isoform- or class-selective HDAC inhibitors during the last four years, as well as the therapeutic potential of these compounds. Expert opinion: HDACs represent one of the most promising therapeutic targets, particularly for tumor therapy though their roles in cancer are still blurry. From 2012 to present, along with the advances of structural biology and homology models, lots of isoform- or class-selective HDAC inhibitors, such as hydroxamic acids and benzamides with various capping groups were found, providing a promising way to circumvent drug toxicity and side-effect issues, as well as providing chemical probes for further better understanding of the biological process related to specific isoform.

Metastatic colorectal cancer (mCRC) is a major cause of cancer-related mortality due to the absence of effective therapeutics. Thus, it is urgent to discover new drugs for mCRC. Fucosyltransferase 8 (FUT8) is a potential therapeutic target with high level in most malignant cancers including CRC. FUT8 mediates the core fucosylation of CD276 (B7-H3), a key immune checkpoint molecule (ICM), in CRC. FUT8-silence-induced defucosylation at N104 on B7-H3 attracts heat shock protein family A member 8 (HSPA8, also known as HSC70) to bind with 106-110 SLRLQ motif and consequently propels lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway. Then we report the development and characterization of a potent and highly selective small-molecule inhibitor of FUT8, named FDW028, which evidently prolongs the survival of mice with CRC pulmonary metastases (CRPM). FDW028 exhibits potent anti-tumor activity by defucosylation and impelling lysosomal degradation of B7-H3 through the CMA pathway. Taken together, FUT8 inhibition destabilizes B7-H3 through CMA-mediated lysosomal proteolysis, and FDW028 acts as a potent therapeutic candidate against mCRC by targeting FUT8.

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y₁₄R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y₁₄R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y₁₄R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y₁₄R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y₁₄R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y₁₄R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y₁₄R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.