This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 ( BRCA1/2 ) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

Gastric cancer (GC) is currently the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs), transcriptional products with more than 200 nucleotides, are not as well-characterized as protein-coding RNAs. Accumulating evidence has recently revealed that maladjustments of diverse lncRNAs may play key roles in multiple genetic and epigenetic phenomena in GC, affecting all aspects of cellular homeostasis, such as proliferation, migration, and stemness. However, the full extent of their functionality remains to be clarified. Considering the lack of viable biomarkers and therapeutic targets, future research should be focused on unravelling the intricate relationships between lncRNAs and GC that can be translated from bench to clinic. Here, we summarized the state-of-the-art advances in lncRNAs and their biological functions in GC, and we further discuss their potential diagnostic and therapeutic roles. We aim to shed light on the interrelationships between lncRNAs and GC with respect to their potential therapeutic applications. With better understanding of these relationships, the biological functions of lncRNAs in GC development will be exploitable, and promising new strategies developed for the prevention and treatment of GC.

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Objectives Autophagy, a highly conserved lysosomal degradation process in eukaryotic cells, has been widely reported closely related to the progression of many types of human cancers, including LGG; however, the intricate relationship between autophagy and LGG remains to be clarified. Materials and methods Multi‐omics methods were used to integrate omics data to determine potential autophagy regulators in LGG. The expression of ZFP36L2 and RAB13 in SW1088 cells was experimentally manipulated using cDNAs and small interfering RNAs (siRNA). RT‐qPCR detects RNAi gene knockout and cDNA overexpression efficiency. The expression levels of proteins in SW1088 cells were evaluated using Western blot analysis and immunofluorescence analysis. Homology modelling and molecular docking were used to identify compounds from Multi‐Traditional Chinese Medicine (TCM) Databases. The apoptosis ratios were determined by flow cytometry analysis of Annexin‐V/PI double staining. We detect the number of autophagosomes by GFP‐MRFP‐LC3 plasmid transfection to verify the process of autophagy flow. Results We integrated various omics data from LGG, including EXP, MET and CNA data, with the SNF method and the LASSO algorithm, and identified ZFP36L2 and RAB13 as positive regulators of autophagy, which are closely related to the core autophagy regulators. Both transcription level and protein expression level of the four autophagy regulators, including ULK1, FIP200, ATG16L1 and ATG2B, and LC3 puncta were increased by ZFP36L2 and RAB13 overexpression. In addition, RAB13 participates in autophagy through ATG2B, FIP200, ULK1, ATG16L1 and Beclin‐1. Finally, we screened multi‐TCM databases and identified gallic acid as a novel potential RAB13 inhibitor, which was confirmed to negatively regulate autophagy as well as to induce cell death in SW1088 cells. Conclusion Our study identified the key autophagic regulators ZFP36L2 and Rab13 in LGG progression, and demonstrated that gallic acid is a small molecular inhibitor of RAB13, which negatively regulates autophagy and provides a possible small molecular medicine for the subsequent treatment of LGG.

Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.