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Protein kinases are key regulators of cellular function and constitute one of the largest and participate in orch estrating the vast majority of cellular activities, forming a criss-cross regulatong network. Kinases, which play a key role in regulating the activity of cellular proteins, are prime targets for anticancer drugs because their abnormal forms can promote the proliferation of tumor cells. Polo-like kinase-1 (Plk-1) is a member of the polo-like family of serine/threonine (Ser/Thr) kinases, which is involved in many aspects of the mitotic process that regulates cell proliferation, which is one of the key kinases of cell mitosis, whose overexpression is closely related to the occurrence and development of many human cancers. Drug development targeting Plk-1 may be one of the promising directions for the treatment of cancer. This review will summarize the structural features of Plk-1 and the cellular processes involved, as well as the rationale for anti-tumor therapy against Plk-1, the latest progress in inhibitor development and the latest strategies.
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PD-1 and PD-L1 antibodies have brought about extraordinary clinical benefits for cancer patients, and their indications are expanding incessantly. Currently, most PD-1/PD-L1 agents are administered intravenously, which may be uncomfortable for some cancer patients. Herein, we develop a novel oral-delivered small molecular, YPD-29B, which specifically targets human PD-L1. Our data suggested that YPD-29B could potently and selectively block the interaction between PD-L1 and PD-1, but did not inhibit any other immune checkpoints. Mechanistically, YPD-29B induced human PD-L1 dimerization and internalization, which subsequently activated T lymphocytes and therefore overcomes immunity tolerance in vitro. YDP-29B was modified as the YPD-30 prodrug to improve druggability. Using humanized mice with human PD-1 xenografts of human PD-L1 knock-in mouse MC38 cancer cells, we demonstrated that YPD-30 exhibited significant antitumor activity and was well tolerated in vivo. Taken together, our results indicate that YPD-30 serves as a promising therapeutic candidate for anti-human PD-L1 cancer immunotherapy.
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RNA binding protein (RBP) plays a key role in gene regulation and participate in RNA translation, modification, splicing, transport and other important biological processes. Studies have shown that abnormal expression of RBP is associated with a variety of diseases. The Musashi (Msi) family of mammals is an evolutionarily conserved and powerful RBP, whose members Msi1 and Msi2 play important roles in the regulation of stem cell activity and tumor development. The Msi family members regulate a variety of biological processes by binding and regulating mRNA translation, stability and downstream cell signaling pathways, and among them, Msi2 is closely related to embryonic growth and development, maintenance of tumor stem cells and development of hematological tumors. Accumulating evidence has shown that Msi2 also plays a crucial role in the development of solid tumors, mainly by affecting the proliferation, invasion, metastasis and drug resistance of tumors, involving Wnt/β-catenin, TGF-β/SMAD3, Akt/mTOR, JAK/STAT, Numb and their related signaling pathways (Notch, p53, and Hedgehog pathway). Preclinical studies of Msi2 gene as a therapeutic target for tumor have achieved preliminary results. This review summarizes the molecular structure, physiological function, role of Msi2 in the development and progression of various solid tumors and the signaling pathways involved.
Subject(s)
Animals , Hedgehog Proteins , Mammals/metabolism , Neoplasms/genetics , Neoplastic Stem Cells , RNA-Binding Proteins/metabolism , Signal TransductionABSTRACT
Follicular lymphoma is an indolent malignant tumor originating from lymph nodes and lymphoid tissues, which may affect the patients' quality of survival due to the recurrence and progression. In recent years, with the deepening understand of the molecular biology and signaling pathways, many new targeted drugs for follicular lymphoma have been discovered, such as monoclonal antibodies, checkpoint inhibitors, epigenetic regulation related targeted therapies and signaling pathway inhibitors. In this review, the new progress of immunotherapy for follicular lymphoma is summarized briefly.
Subject(s)
Humans , Antineoplastic Agents/pharmacology , Epigenesis, Genetic , Immunologic Factors/therapeutic use , Immunotherapy , Lymphoma, Follicular/drug therapyABSTRACT
As a pleiotropic cytokine, interleukin-6 (IL-6) participates in many physiological activities in vivo. IL-6 plays an important role in the physiology and pathology of chronic inflammation, autoimmune diseases, tumors and other diseases through diverse mechanisms. At present, inhibitors targeting IL-6/IL-6R have been shown to improve treatments for some inflammatory diseases such as rheumatoid arthritis and systemic juvenile idiopathic arthritis. IL-6 binds to a specific receptor to activate the downstream JAK/STAT3 signaling pathway. However abnormally activated STAT3 often appears in various types of malignant tumors and participates in the occurrence and development of tumors. In addition, studies have shown that IL-6 is a key factor in the cytokine storm associated with COVID-19 patients. The physiological participation of IL-6/STAT3 pathway in complex diseases makes this pathway become a research hotspot for drug discovery. Therefore, we summarize the latest research progress of small molecular inhibitors on IL-6/STAT3 signaling pathway, in order to provide a reference for the development of IL-6/STAT3 related drug in the future.
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Aim: To study the anti-esophageal cancer activity of a pan-HDAC inhibitor JNJ-26481585 and its molecular mechanism. Methods: Esophageal cancer cell line TE-1 was treated with vehicle control or serial dilutions of JNJ-26481585, and then MTT and colony formation assay, EdU incorporayion assay, and flow cytometry were performed to detect cell viability, cell proliferation, cell cycle and apoptosis, respectively. The anti-metastasis activity of JNJ-26481585 was assessed according to wound healing assay and Transwell invasion assay. Additionally, Western blot was performed to detect the influence of JNJ-26481585 on the growth-related signaling pathways of esophageal cancer. Results: JNJ-26481585 effectively inhibited cellular viability and proliferation of TE-1 cells, as well as induced G2/M phase arrest and apoptosis even at low treatment concentrations. Meanwhile, it also had the ability to suppress the migration and invasion of TE-1 cells. The results of Western blotting indicated that JNJ-26481585 treatment could significantly up-regulate the expression level of P21 protein in TE-1 cells, and inhibit the phosphorylation of Akt and ERK, the pivotal proteins of PI3K/mT0R and MAPK pathways, respectively. Conclusions: JNJ-26481585 exerts its anti-esophageal cancer effects through multiple molecular mechanisms, including up-regulation of cell cycle inhibitor P21 and blockade of Akt/mTOR and ERK signaling cascades.
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Objective:This study aims to explore the anticancer effects and potential mechanisms of HJC0152, a novel STAT3 inhibitor, on the invasion and migration capacities of human head and neck squamous cell carcinoma (HNSCC) cell lines in vitro. Methods:Cells were divided into two groups, the dimethyl sulfoxide (DMSO) group and the HJC0152 group in which HNSCC cell lines UM-1 and SCC-15 were treated with DMSO or HJC0152 for 24 h. The total expression levels of STAT3, p-STAT3 (Tyr705/Ser727), MMP-2/9, N/E-cadherin, TWIST1, and vimentin;and the cytoplasm and nuclear expression levels of STAT3 and p-STAT3 (Tyr705/Ser727) were detected by Western blot assay. Wound healing and Transwell assays were employed to detect the invasion and migration abilities of the UM-1 and SCC-15 cells. The expression and location of N/E-cadherin were visualized by immunofluorescence staining. Results:Western blot indicated that the total expression of p-STAT3 (Tyr705), MMP-2/9, N-cadherin, TWIST1, and vimentin were significantly declined and that E-cadherin was remarkably elevated in the HJC0152 group cells compared with that of the DMSO group, with no difference in STAT3 or p-STAT3 (Ser727). Cytoplasm and nuclear STAT3 (Tyr705) were also inhibited by HJC0152. Wound healing and Transwel assays indicated that tumor invasion and migration capacities were impressively attenuated in the HJC0152 group cells compared to that of the DMSO group. Conclusion:HJC0152 suppresses the phosphorylation of STAT3 at Tyr705 in the HNSCC cell lines, leading to impair transcription activity, deplete expression levels of target genes, and subsequently inhibit migration and invasion capabilities of HNSCC.
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Objective:This study aims to explore the anticancer effects and potential mechanisms of HJC0152, a novel STAT3 inhibitor, on the invasion and migration capacities of human head and neck squamous cell carcinoma (HNSCC) cell lines in vitro. Methods:Cells were divided into two groups, the dimethyl sulfoxide (DMSO) group and the HJC0152 group in which HNSCC cell lines UM-1 and SCC-15 were treated with DMSO or HJC0152 for 24 h. The total expression levels of STAT3, p-STAT3 (Tyr705/Ser727), MMP-2/9, N/E-cadherin, TWIST1, and vimentin;and the cytoplasm and nuclear expression levels of STAT3 and p-STAT3 (Tyr705/Ser727) were detected by Western blot assay. Wound healing and Transwell assays were employed to detect the invasion and migration abilities of the UM-1 and SCC-15 cells. The expression and location of N/E-cadherin were visualized by immunofluorescence staining. Results:Western blot indicated that the total expression of p-STAT3 (Tyr705), MMP-2/9, N-cadherin, TWIST1, and vimentin were significantly declined and that E-cadherin was remarkably elevated in the HJC0152 group cells compared with that of the DMSO group, with no difference in STAT3 or p-STAT3 (Ser727). Cytoplasm and nuclear STAT3 (Tyr705) were also inhibited by HJC0152. Wound healing and Transwel assays indicated that tumor invasion and migration capacities were impressively attenuated in the HJC0152 group cells compared to that of the DMSO group. Conclusion:HJC0152 suppresses the phosphorylation of STAT3 at Tyr705 in the HNSCC cell lines, leading to impair transcription activity, deplete expression levels of target genes, and subsequently inhibit migration and invasion capabilities of HNSCC.
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To review the research progress of small molecule tyrosine kinase inhibitors (TKIs). Literatures on tyrosine kinase inhibitors which have already been successfully marketed or are in development were sorted and summarized according to the targets and related cancers. Through binding to catalytic domain of intracellular tyrosine kinase, small molecule TKIs inhibit the catalytic activity specifically and block cell proliferation signals, and some of them have already been used in cancer therapy or are in different stages of clinical development, showing good prospects.
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Fibroblast growth factor receptors (FGFRs) are in the superfamily of receptor tyrosine kinases' (RTKs). Fibroblast growth factors (FGFs) bind to FGFRs with high-affinity, involving in many biological processes, such as the regulation of organ development, angiogenesis, cell proliferation, migration and anti-apoptosis. The activating mutations and amplification of the FGFR gene, resulting in FGFR protein amplification, are closely associated with the development and progression of many malignancies in human. In recent years, various small molecule FGFR inhibitors with different chemical backbones are designed, synthesized, and mainly applied to the clinical anti-cancer research. This article is devoted to review of selective second generation of small molecule FGFR inhibitors that are currently used in clinical trials, and the interaction with the FGFR protein, in order to provide strategies to the design of small molecule FGFR inhibitors.
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Aberrant activation of the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(PKB,Akt)-mammalian target of rapamycin(mTOR) pathway is commonly observed in human cancer and is critical for cell survival, proliferation and differentiation.A variety of small molecule inhibitors targeting PI3K-Akt-mTOR pathway are under clinical studies.This review will summarize the recent studies in terms of the PI3K-Akt-mTOR signaling pathway and cancer,research progress of the antitumor activity possessed by PI3K-Akt-mTOR inhibitors,as well as the recent research in the related field conducted by our group.
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Macrophage migration inhibitory factor (MIF) is originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibits the random migration of macrophages. MIF is now recognized as a multipotent cytokine involved in the regulation of immune and inf lammatory responses. In rheumatoid arthritis (RA), MIF promotes inf lammatory responses by inducing proinflammatory cytokines and tissue-degrading molecules, promoting the proliferation and survival of synovial fibroblasts, stimulating neutrophil chemotaxis, and regulating angiogenesis and osteoclast differentiation. Expression of MIF in synovial tissue and synovial fluid levels of MIF are elevated in RA patients. Specifically, MIF levels correlate with RA disease activity and high levels are associated with bone erosion. In animal models of RA, the genetic and therapeutic inhibition of MIF has been shown to control inflammation and bone destruction. Based on the role of MIF in RA pathogenesis, small molecular inhibitors targeting it or its receptor pathways could provide a new therapeutic option for RA patients.
Subject(s)
Humans , Arthritis, Rheumatoid , Chemotaxis , Cytokines , Fibroblasts , Inflammation , Macrophage Migration-Inhibitory Factors , Macrophages , Models, Animal , Neutrophils , Osteoclasts , Synovial Fluid , T-LymphocytesABSTRACT
Objective To explore a novel and highly specific small-molecule TNFβinhibitor by using computer-aid?ed virtual screening and cell-based assays in vitro. Methods Computer-aided drug design and virtual screening were used to design and identify chemical compounds that targeted TNFβbased on the crystal structure of the TNFβ-TNFR1 com?plex. The effect of the small-molecule compound against TNFβ-induced cytotoxicity of L929 cells was detected by MTT as?say, and the efficacy of the compound to inhibit TNFβ-induced apoptosis of L929 cells was determined by flow cytometry as?say. The impact of the compound on L929 cell cycle was examined by Propidium Iodide (PI) staining and flow cytometry, and the influence of the compound on TNFβ-triggered signal pathway was analyzed by Western blot assay and Ultra VIEW VOX 3D Live Cell Imaging System. Results No.35 compound (named as C35 thereafter) could effectively inhibit TNFβ-induced cell death in a dose dependent manner, and the half-maximum inhibition concentration (IC50) was 8.19μmol/L. Furthermore, C35 had lower cytotoxicity and minimal effect on L929 proliferation. Here we further revealed that C35 could affect TNFβ-induced apoptotic pathway by blocking the activation of Caspase 3, and markedly reduce L929 cell apoptosis induced by TNFβ. Conclusion A novel TNFβsmall-molecule inhibitor was identified by combining computer-aided virtual screening with functional assays, and which could block TNFβ-triggered apoptotic pathway and efficiently inhibit the cell death in?duced by TNFβ.
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@#Acute myeloid leukemia(AML)is one of the most common acute leukemias in adults. Those patients with FLT3 mutations have a particularly poor prognosis. Recently, the emergence of a variety of targeted inhibitors has shown the capability of suppressing FLT3 signaling in vivo, which provided a new way to treat AML. In this paper, we reviewed those inhibitors based on their structures, which include indolone-related inhibitors, indolocarbazo-related inhibitors, benzimidazole/benzopyrazole-related inhibitors, quinoline/quinoxaline/quinazoline-related inhibitors, tricyclic inhibitors, pyrimidine-related inhibitors and others.
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Aurora-A is a mitotic serine/threonine kinase that is evolutionally conserved and localized at the centrosome. Aurora-A activation is required for mitotic entry, centrosome maturation, and centrosome separation. Aurora-A is frequently amplified and/or over-expressed in breast, ovarian, esophageal, colon, lung, and bladder cancers. Aurora-A has recently become a new target of malignant tumors. The Aurora-A inhibitor can be combined with other chemotherapeutic drugs to provide a new way for cancer treatment. In this study, we review the function and inhibitor of Aurora-A kinase.
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Dysregulated activation of immune and synovial cells and their reciprocal action play a key role in the pathogenesis of rheumatoid arthritis (RA). Various signal transduction molecules regulate cellular responses and small molecular inhibitors targeting the signal molecules, such as Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors, which have been developed for treating RA. Phosphoinositide 3-kinase (PI3K) is one of the signal molecules, which regulates innate and adaptive immune systems and is over-expressed in RA. PI3Ks phosphorylate phosphoinositide-4,5-bisphosphate (PI-4,5-P2) generates phosphoinositide-3,4,5-triphosphate (PI-3,4,5-P3) at the cell membrane. PI3Ks are divided into class I, II and III. Two catalytic subunits, p110gamma and p110delta of PI3K, modulate cellular development, differentiation, proliferation, migration, cytokine synthesis and antibody production in both innate and adaptive immune systems. In RA synovium and synovial fibroblasts, the expression of p110gamma and p110delta is increased, and their up-regulation results in the abnormal activation of cellular immune responses. In preclinical animal models for RA, genetic deletion of p110gamma and p110delta and selective inhibitors decrease the clinical arthritis score, synovial inflammation, cellular infiltration, bone and cartilage erosion and osteoclast activity. There is a synergistic effect for controlling arthritis by dual inhibition of PI3Kgamma and PI3Kdelta. Through reviewing the function of PI3K in the immune system and the effect of PI3K inhibition in preclinical arthritis animal models, we can expect the PI3K inhibition as a new therapeutic target for treatment of RA.