Hydrogel Applications in the Diagnosis and Treatment of Glioblastoma.

Glioblastoma multiforme (GBM), a common malignant neurological tumor, has boundaries indistinguishable from those of normal tissue, making complete surgical removal ineffective. The blood-brain barrier (BBB) further impedes the efficacy of radiotherapy and chemotherapy, leading to suboptimal treatment outcomes and a heightened probability of recurrence. Hydrogels offer multiple advantages for GBM diagnosis and treatment, including overcoming the BBB for improved drug delivery, controlled drug release for long-term efficacy, and enhanced relaxation properties of magnetic resonance imaging (MRI) contrast agents.

Design and synthesis of the first PARP-1 and proteasome dual inhibitors to treat breast cancer.

PARP-1 is a crucial factor in repairing DNA single strand damage and maintaining genomic stability. However, the use of PARP-1 inhibitors is limited to combination with chemotherapy or radiotherapy, or as a single agent for indications carrying HRR defects. The ubiquitin-proteasome system processes the majority of cellular proteins and is the principal manner by which cells regulate protein homeostasis.

Beyond Loading: Functions of Plant ARGONAUTE Proteins.

ARGONAUTE (AGO) proteins are key components of the RNA-induced silencing complex (RISC) that mediates gene silencing in eukaryotes. Small-RNA (sRNA) cargoes are selectively loaded into different members of the AGO protein family and then target complementary sequences to in-duce transcriptional repression, mRNA cleavage, or translation inhibition. Previous reviews have mainly focused on the traditional roles of AGOs in specific biological processes or on the molecular mechanisms of sRNA sorting.

Discovery of novel reversible inhibitor of DprE1 based on benzomorpholine for the treatment of tuberculosis.

About a quarter of the world's population is infected with , equivalent to about two billion people. With the emergence of multidrug-resistant tuberculosis, those existing anti-tuberculosis drugs no longer meet the demand for cure anymore; there is an urgent need for the development of new anti-tuberculosis drugs. Decaprenylphosphoryl-β-D-ribose 2´-epimerase (DprE1) has been proven to be a potential antimycobacterial target, and several inhibitors have entered clinical trial.

Design, synthesis and biological evaluation of a series of novel pyrrolo[2,3-d]pyrimidin/pyrazolo[3,4-d]pyrimidin-4-amine derivatives as FGFRs-dominant multi-target receptor tyrosine kinase inhibitors for the treatment of gastric cancer.

Gastric cancer is the second most lethal cancer across the world. With the progress in therapeutic approaches, the 5-year survival rate of early gastric cancer can reach > 95%. However, the prognosis and survival time of advanced gastric cancer is still somber.

A Facile Total Synthesis of Kilogram-Scale Production of SKLB1039: A Novel and Selective Hexahydroisoquinolin-Containing EZH2 Inhibitor.

Background: SKLB1039 is a potent, highly selective, and orally bioavailable EZH2 inhibitor, which significantly inhibited breast tumor growth and metastasis in pre-clinical studies. In a previously reported synthesis of SKLB1039, the yields of several steps were low, which led to an overall yield of less than 10%. In addition, flash chromatography was required for the purification of several intermediates using this route.

Design, synthesis and biological evaluation of 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one derivatives as potent FAK inhibitors for the treatment of ovarian cancer.

Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy.

A novel fixed-dose combination treatment for chronic hepatitis C, based on NS5A inhibitor fopitasvir and NS5B inhibitor sofosbuvir.

Drug resistance caused by the extreme genetic variability of zhe hepatitis C virus has rendered effective combinations of drugs indispensable in the treatment of chronic hepatitis C (CHC). Herein, we developed a fixed-dose combination (FDC) treatment containing the NS5B inhibitor sofosbuvir (SOF) and the NS5A inhibitor fopitasvir (FOP). Then the dissolution behavior of FOP in FOP/SOF FDC was improved by co-micronizing FOP with lactose.

Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.

EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity.

Design and synthesis of (E)-1,2-diphenylethene-based EZH2 inhibitors.

Enhancer of zeste homolog 2 (EZH2) serves as the catalytic subunit of the polycomb repression complex 2 (PRC2), which is implicated in cancer progression metastasis and poor prognosis. Based on our EZH2 inhibitor SKLB1049 with low nanomolar activity, we extended the "tail" region to get a series of (E)-1,2-diphenylethene derivatives as novel EZH2 inhibitors. SAR exploration and preliminary assessment led to the discovery of the potent novel EZH2 inhibitor 9b (EZH2 IC = 22.

[A rapid method based on advanced polymer chromatography for analyzing the products of the acid-catalyzed depolymerization of lignosulfonate].

In this study, a fast and efficient method for the separation and analysis of the products in the acid-catalyzed depolymerization of commercially available sodium lignosulfonate has been developed. The depolymerized lignosulfonate products were well separated and characterized by advanced polymer chromatography (APC) employing four ACQUITY APC XT columns in series and a ultraviolet detector. The developed method enabled the detection of relative-low-molecular-mass lignin degradation products with peak molecular weights () of 720, 490, and 260 Da, and an extremely low polydispersity index (PDI) of 1, indicating almost complete conversion of lignosulfonate to smaller molecules.

Rapid determination of lignosulfonate depolymerization products by advanced polymer chromatography.

Depolymerized lignin products are very complex mixtures. Based on a depolymerization solution of commercially available sodium lignosulfonate under mild conditions, a fast and efficient method for the separation and direct characterization of the degree and efficiency of the acid-catalyzed depolymerization of lignin was developed in this study. Using an ultraviolet detector, the depolymerized lignosulfonate products were well separated and characterized according to the relative molar mass distribution on an advanced polymer chromatographic system with three ethylene-bridged hybrid columns having small pore sizes (45 Å) in series and tetrahydrofuran as the mobile phase.

Synthesis and biological evaluation of benzomorpholine derivatives as novel EZH2 inhibitors for anti-non-small cell lung cancer activity.

The histone lysine methyltransferase EZH2 has been reported to play important roles in cancer aggressiveness, metastasis and poor prognosis. In this study, a series of benzomorpholine derivatives were synthesized and biologically evaluated as EZH2 inhibitors. The target compounds were obtained in good yields from 3-amino-5-bromo-2-hydroxybenzoic acid via cyclization, Suzuki coupling and amidation as the key steps.

Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis.

The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy.