Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma.

Adenoviral E1A binding protein 300 kDa (p300) and its closely related paralog CREB binding protein (CBP) are promising therapeutic targets for human cancer. Here, we report the first discovery of novel potent small-molecule PROTAC degraders of p300/CBP against hepatocellular carcinoma (HCC), one of the most common solid tumors. Based upon the clinical p300/CBP bromodomain inhibitor CCS1477, a conformational restriction strategy was used to optimize the linker to generate a series of PROTACs, culminating in the identification of QC-182. This compound effectively induces p300/CBP degradation in the SK-HEP-1 HCC cells in a dose-, time-, and ubiquitin-proteasome system-dependent manner. QC-182 significantly downregulates p300/CBP-associated transcriptome in HCC cells, leading to more potent cell growth inhibition compared to the parental inhibitors and the reported degrader dCBP-1. Notably, QC-182 potently depletes p300/CBP proteins in mouse SK-HEP-1 xenograft tumor tissue. QC-182 is a promising lead compound toward the development of p300/CBP-targeted HCC therapy.

Enantioselective Oral Absorption of Molecular Chiral Mesoporous Silica Nanoparticles.

Inspired by the unique pharmacological effects of chiral drugs in the asymmetrical body environments, it is assumed that the chirality of nanocarriers is also a key factor to determine their oral adsorption efficiency, apart from their size, shape, etc. Herein, l/d-tartaric acid modified mesoporous silica nanoparticles (l/d-CMSNs) are fabricated via a one-pot cocondensation method, and focused on whether the oral adsorption of nanocarriers will be benefited from their chirality. It is found that l-CMSN performed better in the sequential oral absorption processes, including mucus permeation, mucosa bio-adhesion, cellular uptake, intestinal transport and gastrointestinal tract (GIT) retention, than those of the d-chiral (d-CMSN), racemic (dl-CMSN), and achiral (MSN) counterparts. The multiple chiral recognition mechanisms are experimentally and theoretically demonstrated following simple differential adsorption on biointerfaces, wherein electrostatic interaction is the dominant energy. During the oral delivery task, l-CMSN, which is proven to be stable, nonirritative, biocompatible, and biodegradable, is efficiently absorbed into the blood (1.72-2.05-fold higher than other nanocarriers), and helps the loaded doxorubicin (DOX) to achieve better intestinal transport (2.32-27.03-times higher than other samples), satisfactory bioavailability (449.73%) and stronger antitumor effect (up to 95.43%). These findings validated the dominant role of chirality in determining the biological fate of nanocarriers.

Noninvasive preoperative differential diagnosis of gallbladder carcinoma and xanthogranulomatous cholecystitis: A retrospective cohort study of 240 patients.

BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is an extremely rare entity. Due to XGC's clinical and radiological resemblance to gallbladder carcinoma (GBC), intraoperative frozen section during cholecystectomy is often performed to exclude the diagnosis of GBC. Our study is aiming to find a noninvasive indicator of XGC. To our knowledge, this is the largest XGC cohort ever studied. METHODS: This study retrospectively collected clinical characteristics, serological tests, and imaging features of 150 GBC patients and 90 XGC patients. The diagnosis of these 150 GBC patients and 90 XGC patients was based on intraoperative frozen section histopathology. T-test was utilized to compare differences between XGC and GBC. Receiver operating characteristic (ROC) curve was conducted and the area under the curve (AUC) was managed to evaluate the validity. RESULTS: The carcinoembryonic antigen (CEA) level in blood tests was significantly elevated in GBC patients than in XGC patients (p = 0.007). The presence of submucosal hypo-attenuated nodules (80% in XGC, 16% in GBC, p < 0.001), low density border (60% in XGC, 21% in GBC, p = 0.001), and nodular thickening in the bottom of the gallbladder with calcification (70% in XGC, 37% in GBC, p = 0.004) is significantly associated with XGC patients, whereas massive hilar infiltration (0% in XGC, 21% in GBC, p < 0.001), multiple lymph nodes in the hilar area (10% in XGC, 72% in GBC, p = 0.001), and gallbladder mucosal line continuity (50% in XGC, 95% in GBC, p = 0.002) are highly associated with GBC patients. The ROC curve was performed and the gallbladder mucosal line continuity (AUC = 0.708) and the AUC of low density border around the occupation (AUC = 0.654) showed a good prediction of XGC. CONCLUSIONS: Gallbladder mucosal line continuity and low density border around the occupation presented good indication value for the diagnosis of XGC. Our study proposed a noninvasive differential diagnosis method for XGC and GBC.

Impacts of Cigarette Smoking Status on Metabolomic and Gut Microbiota Profile in Male Patients With Coronary Artery Disease: A Multi-Omics Study.

Background: Cigarette smoking has been considered a modifiable risk factor for coronary artery disease (CAD). Changes in gut microbiota and microbe-derived metabolites have been shown to influence atherosclerotic pathogenesis. However, the effect of cigarette smoking on the gut microbiome and serum metabolites in CAD remains unclear. Method: We profiled the gut microbiota and serum metabolites of 113 male participants with diagnosed CAD including 46 current smokers, 34 former smokers, and 33 never smokers by 16S ribosomal RNA (rRNA) gene sequencing and untargeted metabolomics study. A follow-up study was conducted. PICRUSt2 was used for metagenomic functional prediction of important bacterial taxa. Results: In the analysis of the microbial composition, the current smokers were characterized with depleted Bifidobacterium catenulatum, Akkermansia muciniphila, and enriched Enterococcus faecium, Haemophilus parainfluenzae compared with the former and never smokers. In the untargeted serum metabolomic study, we observed and annotated 304 discriminant metabolites, uniquely including ceramides, acyl carnitines, and glycerophospholipids. Pathway analysis revealed a significantly changed sphingolipids metabolism related to cigarette smoking. However, the change of the majority of the discriminant metabolites is possibly reversible after smoking cessation. While performing PICRUSt2 metagenomic prediction, several key enzymes (wbpA, nadM) were identified to possibly explain the cross talk between gut microbiota and metabolomic changes associated with smoking. Moreover, the multi-omics analysis revealed that specific changes in bacterial taxa were associated with disease severity or outcomes by mediating metabolites such as glycerophospholipids. Conclusions: Our results indicated that both the gut microbiota composition and metabolomic profile of current smokers are different from that of never smokers. The present study may provide new insights into understanding the heterogenic influences of cigarette smoking on atherosclerotic pathogenesis by modulating gut microbiota as well as circulating metabolites.