Discovery of a Highly Potent PROTAC Degrader of p300/CBP Proteins for the Treatment of Enzalutamide-Resistant Prostate Cancer.

Prostate cancer therapies against androgen receptor (AR) eventually develop lethal resistance; thus, exploring new therapeutic approaches is urgent for prostate cancer treatment. Acetyltransferase p300/CBP are key coactivators for AR-mediated transcription and represent promising therapeutic targets to inhibit AR activity in prostate cancer. We describe the design synthesis and evaluation of a new class of p300/CBP PROTAC degraders. We identified an excellent p300/CBP degrader MJP6412, which effectively induced degradation of p300/CBP proteins, downregulated AR target genes, and inhibited cell growth of human prostate cancer cell lines and enzalutamide-resistant cells with IC50 even at nanomolar concentrations. Furthermore, MJP6412 demonstrated significant inhibition of tumor growth in a VCaP xenograft model. Collectively, MJP6412 is a promising lead compound for the treatment of prostate cancer, especially enzalutamide-resistant prostate cancer.

Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis.

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14, 4-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

Effects of Dezocine and Sufentanil on Th1/Th2 Balance in Breast Cancer Patients Undergoing Surgery.

BACKGROUND: It is very important for breast cancer patients undergoing surgery to choose an opioid that has little effect on the immune system. The aim of this study is to compare the effects of dezocine or sufentanil on postoperative pain and Th1/Th2 balance in patients undergoing breast cancer surgery. METHODS: Data from 92 breast cancer patients from January 2019 to July 2020 at Foshan Second People's Hospital (Guangdong, China) were analyzed. Sufentanil (SF) was used in group SF (n = 44) and dezocine (DE) in group DE (n = 48). The Visual Analog Scale (VAS) scores were assessed, and the percentages of Th1 cells and Th2 cells in peripheral blood were detected before anesthesia and at 2, 12, 24, and 48 hours after surgery. RESULTS: There was no significant difference in the VAS scores between the two groups at 2, 24, and 48 hours after surgery (P > 0.05). The VAS scores at 12 hours after surgery in group DE were significantly lower than those in group SF with a statistically significant difference (P < 0.05). The percentage of Th1 cells in group DE at 2, 12, 24, and 48 hours after surgery was significantly lower than that in group SF (P < 0.05). The percentage of Th2 cells in group DE at 2, 12, 24, and 48 hours after surgery was significantly lower than that in group SF (P < 0.05). The Th1/Th2 ratio at 2, 12, 24, and 48 hours after surgery was significantly higher in group DE than that in group SF (P < 0.05). CONCLUSION: Dezocine for anesthesia induction and postoperative analgesia can maintain the balance of Th1/Th2 more stable than, with the same analgesia efficacy as, sufentanil during the early postoperative period in breast cancer patients undergoing surgery.

Activation of the ROCK1/MMP-9 pathway is associated with the invasion and poor prognosis in papillary thyroid carcinoma.

Rho-associated protein kinase 1 (ROCK1), a serine/threonine kinase, has previously been shown to be over-expressed in various types of human malignant tumors and to play an important role in cancer development and progression. Although ROCK1 has gained growing prominence as an important protein kinase in cancer biology, its potential as a predictive biomarker and a therapeutic target in papillary thyroid carcinoma (PTC) remains unknown. In the present study, ROCK1 expression was examined in 356 formalin-fixed, paraffin-embedded papillary thyroid carcinoma tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Our results showed that ROCK1 expression was significantly increased in PTC compared with normal tissues, and was significantly associated with tumor size, lymphatic metastasis, distant organ metastasis, extrathyroid invasion, vascular invasion and tumor, node and metastasis (TNM) stage. Patients with strong ROCK1 expression had lower overall survival, disease-free survival, lymph node recurrence-free survival and distant recurrence-free survival rates than those with weak expression. Furthermore, overexpression of ROCK1 in papillary thyroid carcinoma cells was found to increase their invasiveness. Silencing ROCK1 by siRNA, however, caused an inhibition of cell invasion. Knockdown of ROCK1 decreased the volume and weight of the xenograft tumors, while overexpression of ROCK1 showed a proliferative tendency with significantly greater tumor volume and weight in vivo. Moreover, the upregulation of ROCK1 increased the expression of MMP-9, and levels of MMP-9 positively correlated with the ROCK1 levels in PTC tissues, implicating that MMP-9 may be involved in the mechanism of ROCK1 in the development and progression of PTC. These data suggest that ROCK1 might be a potential prognostic marker and therapeutic target for the treatment of PTC.

CHI3L1 overexpression is associated with metastasis and is an indicator of poor prognosis in papillary thyroid carcinoma.

OBJECTIVE: In this study, we examined the relationships between the expression level of CHI3L1 and the clinicopathological characteristics of papillary thyroid carcinoma. METHODS: A total of 322 tissue samples from patients with papillary thyroid carcinoma were collected, and the CHI3L1 expression levels in tumor tissues, matched adjacent noncancerous tissues were detected using immunohistochemistry (IHC) and qRT-PCR. The relationships between CHI3L1 expression levels and the clinical characteristics were evaluated. RESULTS: CHI3L1 expression was significantly increased in papillary thyroid carcinoma compared with matched adjacent noncancerous tissues (P< 0.001), tumor tissues with lymph node metastasis (LNM) compared with tumor tissues without LNM (P< 0.001) and tumor tissues with distant organ metastasis (DOM) compared with tumor tissues without DOM (P< 0.01). CHI3L1 expression was significantly associated with tumor size (P= 0.0001), lymph node metastasis (P< 0.0001), distant organ metastasis (P< 0.0001), extrathyroid invasion (P= 0.0022), vascular invasion (P= 0.0004) and TNM stage (P= 0.0001). CHI3L1 overexpression in papillary thyroid carcinoma tissues correlates with the tumor malignant potential (P< 0.01). More importantly, Cox multifactor analysis indicated that patients with high CHI3L1 expression have lower overall survival, disease-free survival, lymph node recurrence-free survival, and distant recurrence free survival rates than those with low expression (P< 0.05). And our findings were further validated by online Oncomine database. CONCLUSIONS: CHI3L1 is associated with tumor metastasis and might be a prognostic biomarker for papillary thyroid carcinoma.