Recent advances in the design of small molecular drugs with acrylamides covalent warheads.

In the development of covalent inhibitors, acrylamides warhead is one of the most popular classes of covalent warheads. In recent years, researchers have made different structural modifications to acrylamides warheads, resulting in the creation of fluorinated acrylamide warheads and cyano acrylamide warheads. These new warheads exhibit superior selectivity, intracellular accumulation, and pharmacokinetic properties. Additionally, although ketoamide warheads have been applied in the design of covalent inhibitors for viral proteins, it has not received sufficient attention. Combined with the studies in kinase inhibitors and antiviral drugs, this review presents the structural features and the progression of acrylamides warheads, offering a perspective on future research and development in this field.

A novel benzothiazole derivative induces apoptosis via the mitochondrial intrinsic pathway producing antitumor activity in colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common malignancies causing the third highest mortality rate in the world. It is particularly urgent to explore effective therapeutic strategies to overcome this disease. We identified a novel benzothiazole derivative (BTD) that may serve as a potentially effective agent against CRC. Method: MTT assays, cell colony formation assays, EdU staining assays, flow cytometry, RNA-seq, Western blotting, and migration and invasion assays were used to examine the effects of BTD on cell proliferation, apoptosis, metastasis, and the cell cycle. The antitumor activity of BTD in vivo was investigated in a CT26 tumor-bearing mouse model. Immunohistochemistry (IHC) was performed to examine the protein expression in mouse tumors. Hematology, biochemical analysis, and H&E staining were used to assess the biosafety of BTD. Results: We observed that BTD suppressed cell proliferation and metastasis and promoted the apoptosis of tumor cells in vitro. Treatment with BTD at a tolerable dose significantly reduced tumor growth in CT26-tumor-bearing mice and appeared to be safe. Treatment of BTD induced apoptosis by increasing the generation of reactive oxygen species (ROS) and evoking the loss of mitochondrial transmembrane potential. Overall, BTD suppressed cell proliferation and metastasis, and induced apoptosis of colorectal tumor cells through the ROS-mitochondria-mediated apoptotic pathway. The preliminary proof of the antitumor activity and relative safety of BTD were validated in a mouse model. Conclusion: Our findings suggest that BTD could serve as a potentially safe and effective candidate for CRC treatment.

Bio-Responsive Macromolecular Drug and Small-Molecular Drug Conjugates: Nanoparticulate Prodrugs for Tumor Microenvironment Heterogeneity Management and Therapeutic Response Enhancement.

How to break through the poor response of current drug therapy, which often resulted from tumor microenvironment heterogeneity (TMH), remains an enormous challenge in the treatment of critical diseases. In this work, a practical solution on bio-responsive dual-drug conjugates for overcoming TMH and improving antitumor treatment, which integrates the advantages of macromolecular drugs and small-molecular drugs, is proposed. Nanoparticulate prodrugs based on small-molecular drug and macromolecular drug conjugates are designed as a robust weapon for programmable multidrug delivery at tumor-specific sites: the tumor microenvironment acid condition triggers delivery of macromolecular aptamer drugs (AX102) to manage TMH (including tumor stroma matrix, interstitial fluid pressure, vasculature network, blood perfusion, and oxygen distribution), and intracellular lysosomal acid condition activates rapid release of small-molecular drugs (doxorubicin and dactolisib) to enhance curative effects. As compared with doxorubicin chemotherapy, the tumor growth inhibition rate is enhanced by 47.94% after multiple tumor heterogeneity management. This work verifies that the nanoparticulate prodrugs facilitate TMH management and therapeutic response enhancements, as well as elucidates synergetic mechanisms for drug resistance reversal and metastasis inhibition. It is hoped that the nanoparticulate prodrugs will be an excellent demonstration of the co-delivery of small-molecular drugs and macromolecular drugs.

Anoikis-related long non-coding RNA signatures to predict prognosis and small molecular drug response in cervical cancer.

Background: Cervical cancer (CC) is a major health threat to females, and distal metastasis is common in patients with advanced CC. Anoikis is necessary for the development of distal metastases. Understanding the mechanisms associated with anoikis in CC is essential to improve its survival rate. Methods: The expression matrix of long non-coding RNAs (lncRNAs) from cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) patients was extracted from The Cancer Genome Atlas (TCGA), and highly relevant anoikis-related lncRNAs (ARLs) were identified by the single sample gene set enrichment analysis (ssGSEA) method. ARLs-related molecular subtypes were discerned based on prognosis-related ARLs. ARLs-related prognostic risk score (APR_Score) was calculated and risk model was constructed using LASSO COX and COX models. In addition, we also assessed immune cell activity in the immune microenvironment (TME) for both subtypes and APR_Score groups. A nomogram was utilized for predicting improved clinical outcome. Finally, this study also discussed the potential of ARLs-related signatures in predicting response to immunotherapy and small molecular drugs. Results: Three ARLs-related subtypes were identified from TCGA-CESC (AC1, AC2, and AC3), with AC3 patients having the highest ARG scores, higher angiogenesis scores, and the worst prognosis. AC3 had lower immune cell scores in TME but higher immune checkpoint gene expression and higher potential for immune escape. Next, we constructed a prognostic risk model consisting of 7-ARLs. The APR_Score exhibited a greater robustness as an independent prognostic indicator in predicting prognosis, and the nomogram was a valuable tool for survival prediction. ARLs-related signatures emerged as a potential novel indicator for immunotherapy and small molecular drug selection. Conclusion: We firstly constructed novel ARLs-related signatures capable of predicting prognosis and offered novel ideas for therapy response in CC patients.

Integrated single-cell and bulk RNA sequencing analysis identifies a cancer-associated fibroblast-related gene signature for predicting survival and therapy in gastric cancer.

As the dominant component of the tumor microenvironment, cancer-associated fibroblasts (CAFs), play a vital role in tumor progression. An increasing number of studies have confirmed that CAFs are involved in almost every aspect of tumors including tumorigenesis, metabolism, invasion, metastasis and drug resistance, and CAFs provide an attractive therapeutic target. This study aimed to explore the feature genes of CAFs for potential therapeutic targets and reliable prediction of prognosis in patients with gastric cancer (GC). Bioinformatic analysis was utilized to identify the feature genes of CAFs in GC by performing an integrated analysis of single-cell and transcriptome RNA sequencing using R software. Based on these feature genes, a CAF-related gene signature was constructed for prognostic prediction by LASSO. Simultaneously, survival analysis and nomogram were performed to validate the prognostic predictive value of this gene signature, and qRT-PCR and immunohistochemical staining verified the expression of the feature genes of CAFs. In addition, small molecular drugs for gene therapy of CAF-related gene signatures in GC patients were identified using the connectivity map (CMAP) database. A combination of nine CAF-related genes was constructed to characterize the prognosis of GC, and the prognostic potential and differential expression of the gene signature were initially validated. Additionally, three small molecular drugs were deduced to have anticancer properties on GC progression. By integrating single-cell and bulk RNA sequencing analyses, a novel gene signature of CAFs was constructed. The results provide a positive impact on future research and clinical studies involving CAFs for GC.

Strategies for developing PD-1 inhibitors and future directions.

PD-L1/PD-1 signaling pathway is unarguably the hottest target for developing therapeutics against various types of cancers. With elucidation of crystal structure of PD-1/PD-L1, inhibitors targeting PD-1, PD-L1 or protein-protein interaction between them have been reported. Identification of transcription factors responsible for transcription of mRNA encoding PD-1 and PD-L1 promoted developing inhibitors to downregulate expression of either gene. Elucidation of PD-1 signaling pathway broadened strategies for drug design, for example to interfere recruitment of SHP2 by PD-1. Post-transcription modification (PTM) of phosphorylation, glycosylation, ubiquination and palmitoylation have been reported to modulate the function or homeostasis of proteins of PD-1 or PD-L1. Drugs targeting elements responsible for these PTM have been reported to enhance T cell mediated immunity. Moreover, cleverly designed protein-degrading reagents, either macromolecules or small chemicals (PROTACs) have been tried against PD-1 or PD-L1. In this review we will talk about crystal structure of PD-1/PD-L1, PD-1 signaling pathway, and physiological and pathological roles played by PD-1. Particular attention is paid on strategies for developing drugs targeting PD-1 pathways. For future directions of strategies for developing PD-1/PD-L1 inhibitors, we suggest two realistic fields: bi-functional or multi-functional small molecules; nano-material to deliver siRNAs. With recent identification of many more checkpoints in T cells through genome-wide screening and harnessing the power of nano-materials to pack multiple siRNAs, tumor microenvironment T cell specific mano-materials containing siRNAs against PD-1 and other checkpoints simultaneously could be of particular interest to industry.

pH-responsive stearic acid-O-carboxymethyl chitosan assemblies as carriers delivering small molecular drug for chemotherapy.

Recently, chemotherapy is still widely exploited to treat the residual, infiltrative tumor cells after surgical resection. However, many anticancer drugs are limited in clinical application due to their poor water-solubility (hydrophibic) and stability, low bioavailability, and unfavorable pharmacokinetics. Herein, an amphiphilic stearic acid-O-carboxymethyl chitosan (SA-CMC) conjugate was synthesized by amide linkage of SA to the backbone of CMC polymer and then self-assembled into nanoparticles (SA-CMC NPs) with the hydrodynamic particle size of ~100 nm. Subsequently, Paclitaxel (PTX) as a potent and broad-spectrum anticancer drug was loaded into SA-CMC NPs by a probe sonication combined with dialysis method. Owing to the multi-hydrophobic inner cores, the prepared PTX-SA-CMC NPs showed a considerable drug-loading capacity of ~19 wt% and a biphasic release behavior with an accumulative release amount in the range of 70-90% within 72 h. PTX-SA-CMC NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of acid, PTX-SA-CMC NPs showed exceptional instability by pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with Cremophor EL-based free PTX treatment, PTX-SA-CMC NPs under pH-stimuli accomplished highly efficient apoptosis in cancer cells and effectively suppression of tumors by chemotherapy. Overall, PTX-SA-CMC NPs integrating imaging capacity might be a simple yet feasible PTX nanosystem for tumor-targeted delivery and cancer therapy.

Light/pH-Triggered Biomimetic Red Blood Cell Membranes Camouflaged Small Molecular Drug Assemblies for Imaging-Guided Combinational Chemo-Photothermal Therapy.

Nanoparticles camouflaged by red blood cell (RBC) membranes have attracted considerable attention owing to reservation of structure of membrane and surface proteins, endowing prominent cell-specific function including biocompatibility, prolonged circulation lifetime, and reduced reticular endothelial system (RES) uptake ability. Considering the drawbacks of carrier-free nanomedicine including the serious drug burst release, poor stability, and lack of immune escape function, herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin (10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged circulation, controlled drug release, and synergistic chemo-photothermal therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs) exhibited a diameter of ∼150 nm with core-shell structure, high drug payload (∼92 wt %), and reduced RES uptake function. Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of near-infrared laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional instability by heat-mediated membrane disruption and pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli accomplished highly efficient apoptosis in cancer cells and remarkable ablation of tumors by chemo-PTT. This biomimetic nanoplatform based on carrier-free, small molecular drug coassemblies integrating imaging capacity as a promising theranostic system provides potential for cancer diagnosis and combinational therapy.