Spatial transcriptomics in development and disease.

The proper functioning of diverse biological systems depends on the spatial organization of their cells, a critical factor for biological processes like shaping intricate tissue functions and precisely determining cell fate. Nonetheless, conventional bulk or single-cell RNA sequencing methods were incapable of simultaneously capturing both gene expression profiles and the spatial locations of cells. Hence, a multitude of spatially resolved technologies have emerged, offering a novel dimension for investigating regional gene expression, spatial domains, and interactions between cells.

Discovery, Synthesis, and Evaluation of Novel Dual Inhibitors of a Vascular Endothelial Growth Factor Receptor and Poly(ADP-Ribose) Polymerase for BRCA Wild-Type Breast Cancer Therapy.

Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of breast cancer (BC) with breast cancer susceptibility (BRCA) gene mutation. Leveraging new synthetic lethal interactions may be an effective way to broaden the indication of PARP inhibitors for BC patients with wild-type BRCA. Vascular endothelial growth factor receptor (VEGFR)-mediated suppression of angiogenesis has been reported to improve the sensitivity of wild-type BRCA cells to PARP inhibitors through synthetic lethality.

Protein-level mutant p53 reporters identify druggable rare precancerous clones in noncancerous tissues.

Detecting and targeting precancerous cells in noncancerous tissues is a major challenge for cancer prevention. Massive stabilization of mutant p53 (mutp53) proteins is a cancer-specific event that could potentially mark precancerous cells, yet in vivo protein-level mutp53 reporters are lacking. Here we developed two transgenic protein-level mutp53 reporters, p53-Akaluc and p53-mCherry, that faithfully mimic the dynamics and function of mutp53 proteins in vivo.

Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy.

The effective potency and resistance of poly(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here, we exploit a new paradigm that mimics the effects of breast cancer susceptibility genes (BRCA) mutations to trigger the possibility of synthetic lethality, based on the previous discovery of a potential synthetic lethality effect between bromodomain-containing protein 4 (BRD4) and PARP1. Consequently, the present study describes compound with high selectivity for BRD4 and PARP1.

Targeting Bromodomain-Selective Inhibitors of BET Proteins in Drug Discovery and Development.

Blocking the interactions between bromodomain and extraterminal (BET) proteins and acetylated lysines of histones by small molecules has important implications for the treatment of cancers and other diseases. Many pan-BET inhibitors have shown satisfactory results in clinical trials, but their potential for poor tolerability and toxicity persist. However, recently reported studies illustrate that some BET bromodomain (BET-BD1 or BET-BD2)-selective inhibitors have advantage over pan-inhibitors, including reduced toxicity concerns.

Targeting Autophagy-Related Epigenetic Regulators for Cancer Drug Discovery.

Existing evidence has demonstrated that epigenetic modifications (including DNA methylation, histone modifications, and microRNAs), which are associated with the occurrence and development of tumors, can directly or indirectly regulate autophagy. In particular, nuclear events induced by several epigenetic regulators can regulate the autophagic process and expression levels of tumor-associated genes, thereby promoting tumor progression. Tumor-associated microRNAs, including oncogenic and tumor-suppressive microRNAs, are of great significance to autophagy during tumor progression.

Discovery, Synthesis, and Evaluation of Highly Selective Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Inhibitor for the Potential Treatment of Metastatic Triple-Negative Breast Cancer.

We herein report the identification, structural optimization, and structure-activity relationship of thieno[2,3-]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. -(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)thieno[2,3-]pyrimidin-4-yl)piperazine-1-carboxamide () was the most potent VEGFR3 inhibitor (IC = 110.4 nM) among developed compounds.

Targeting Atg4B for cancer therapy: Chemical mediators.

Atg4, a pivotal macroautophagy/autophagy-related cysteine protein family, which regulate autophagy through either cleaving Atg8 homologs for its further lipidation or delipidating Atg8 homologs from the autophagosome. There are four homologs, Atg4A, Atg4B, Atg4C, and Atg4D. Among them, an increasing amount of evidence indicates that Atg4B possessed superior catalytic efficiency toward the Atg8 substrate, as well as regulates autophagy process and plays a key role in the development of several human cancers.

Designing an eEF2K-Targeting PROTAC small molecule that induces apoptosis in MDA-MB-231 cells.

Eukaryotic elongation factor 2 kinase (eEF2K) is a key α-kinase that negatively regulates the extension step of protein synthesis, which consumes most of the energy and amino acids required for protein synthesis. Studies have found that eEF2K protein is related to the breast cancer. However, existing inhibitor effect has not achieved the desired effect in cancer therapy.

High-throughput photoelectrochemical determination of E. coli O157:H7 by modulation of the anodic photoelectrochemistry of CdS quantum dots via reversible deposition of MnO.

A method is described for modulating the anodic photoelectrochemistry of netlike CdS quantum dots through the deposition and dissolution of the electron acceptor manganese dioxide (MnO) on the surface of the photoelectrode. Specifically, the photocurrent of a CdS-modified indium tin oxide (ITO/CdS) electrode is inhibited by chemical deposition of MnO. However, the photocurrent becomes recovered by oxidative removal of MnO with HO.