ABSTRACT
BACKGROUND: SHP2 is a protein tyrosine phosphatase that is extensively involved in several signaling pathways related to cancer occurrence, and thus SHP2 has been proposed as an attractive target for cancer treatment. METHODS: After a brief introduction of SHP2, we provided a short overview of the structure, function and regulation mechanism of SHP2 in cancer occurrence. Then, this perspective focused on the current therapeutic strategies targeting SHP2, including SHP2 PTP inhibitors, SHP2 allosteric inhibitors and SHP2-targeting PROTACs, and discussed the benefits and defects of these strategies. Finally, the opportunities and challenges were presented. RESULTS: SHP2 regulated RAS-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 signaling pathways involved in the pathogenesis of cancer via conformations conversion. Current therapeutic strategies targeting SHP2, especially SHP2 allosteric inhibitors, hold significant potency and have broad application prospects for cancer therapy. CONCLUSION: In summary, SHP2 is a promising therapeutic target, and strategies targeting SHP2 offer an alternative program for cancer patients.
Subject(s)
Enzyme Inhibitors , Neoplasms , Humans , Enzyme Inhibitors/chemistry , Neoplasms/drug therapy , Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Signal TransductionABSTRACT
Proteolysis-targeting chimeras (PROTACs) as an emerging drug discovery modality has been extensively concerned in recent years. Over 20 years development, accumulated studies have demonstrated that PROTACs show unique advantages over traditional therapy in operable target scope, efficacy, and overcoming drug resistance. However, only limited E3 ligases, the essential elements of PROTACs, have been harnessed for PROTACs design. The optimization of novel ligands for well-established E3 ligases and the employment of additional E3 ligases remain urgent challenges for investigators. Here, we systematically summarize the current status of E3 ligases and corresponding ligands for PROTACs design with a focus on their discovery history, design principles, application benefits, and potential defects. Meanwhile, the prospects and future directions for this field are briefly discussed.
Subject(s)
Drug Discovery , Ubiquitin-Protein Ligases , Proteolysis , Ligands , Ubiquitin-Protein Ligases/metabolismABSTRACT
Triple-negative breast cancer (TNBC) is one of the most malignant tumors with poor prognosis. Methuosis is a new type of nonapoptotic cell death characterized by the accumulation of cytoplasmic vacuoles. In this study, we synthesized and screened a series of N-phenyl-4-pyrimidinediamine derivatives in TNBC cells, finding that DZ-514 was the best compound with high toxicity independent of the inhibition of BCL6. DZ-514 decreased cell viability, inhibited cell cycle progression, and induced caspase-independent cell death in TNBC cells. Interestingly, DZ-514 induced cytoplasm vacuolation, which could be blocked by Baf A1, the V-ATPase inhibitor. Furthermore, we found that DZ-514-induced vacuoles were derived from macropinosomes rather than autophagosomes. Most importantly, methuosis induced by DZ-514 was partially mediated by activating the ROS-MKK4-p38 axis. Finally, we demonstrated that DZ-514 significantly inhibited tumor growth in an HCC1806 xenograft mouse model. These findings revealed that the novel methuosis inducer DZ-514 could be developed for TNBC treatment.
Subject(s)
Triple Negative Breast Neoplasms , Animals , Humans , Mice , Apoptosis , Cell Death , Cell Line, Tumor , Cell Proliferation , Endosomes/metabolism , Reactive Oxygen Species/metabolism , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays , MAP Kinase Kinase 4/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific and highly effective therapeutic agents. Cancer stem cells (CSCs) are one of the main factors contributing to TNBC relapse and metastasis. Therefore, targeting CSCs selectively with small molecules is a novel strategy for drug development. In this study, the natural product harmine (HM) was identified as a hit compound from 2632 natural product monomers based on phenotypic screening of a 2D assay and patient-derived organoid (PDO) model that was established from a patient who had multiple drug resistance and various visceral and contralateral breast metastases. Next, harmine was further modified and optimized to obtain a lead compound (YH677) with a tetrahydro-ß-carboline scaffold. YH677 showed potent antiproliferative and antimigratory activities against several TNBC cell lines in vitro. In addition, YH677 inhibited epithelial mesenchymal transition (EMT) and stem cell marker expression in a dose-dependent manner. More importantly, YH677 suppressed breast cancer growth and metastasis in orthotopic, metastatic xenograft and patient-derived xenograft (PDX) models in vivo. Mechanistic studies showed that YH677 inhibits the expansion of CSCs by regulating the TGFß/Smad signaling pathway. These preclinical data provide a basis for the development of YH677 as a lead compound for TNBC treatment.
Subject(s)
Triple Negative Breast Neoplasms , Animals , Humans , Triple Negative Breast Neoplasms/pathology , Harmine/metabolism , Harmine/pharmacology , Harmine/therapeutic use , Cell Line, Tumor , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/metabolism , Disease Models, Animal , Cell Proliferation , Signal Transduction , Transforming Growth Factor beta/metabolism , Epithelial-Mesenchymal TransitionABSTRACT
Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuole-presenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.
Subject(s)
Antineoplastic Agents , Triple Negative Breast Neoplasms , Humans , Female , Apoptosis , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell ProliferationABSTRACT
Myoferlin (MYOF) mediates the growth and metastasis of various cancers as an emerging therapeutic target by regulating exocytosis and endocytosis. However, the previously reported MYOF inhibitor, 6y, failed to be a favorable candidate agent due to its poor physicochemical properties, such as water solubility, in preclinical studies. Naturally, a novel range of MYOF inhibitors was synthesized and optimized based on the lead compound 6y. The optimal compound HJ445A potently repressed the proliferation of gastric cancer cells with IC50 values of 0.16 and 0.14 µM in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a KD of 0.17 µM, and HJ445A prevented the migration of gastric cancer cells by reversing the epithelial-mesenchymal transition (EMT) process and inhibited the colony formation of the MKN45 cells in a concentration-dependent manner. Notably, the water solubility of HJ445A was significantly improved compared to 6y, with about 170-fold enhancement. Additionally, HJ445A also demonstrated superior antitumor efficacy in vivo.
Subject(s)
Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Solubility , Water/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Movement , Calcium-Binding Proteins , Membrane Proteins/metabolism , Muscle Proteins/metabolismABSTRACT
B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Drug DevelopmentABSTRACT
Pancreatic cancer is one of the most common cancers with an extremely low survival rate. Metastasis, as one of the key reasons of cancer-related death, is found in more than 50% pancreatic cancer patients at diagnosis. Novel therapeutic targets and drugs blocking cancer metastasis are urgently needed. Herein, we report a series of 1,5-diaryl-1,2,4-triazole derivatives as potent antimetastatic agents. Lead compound 6y displayed effective antimetastatic activities in pancreatic cancer in vitro and in vivo. Concomitant studies indicated that 6y probably binds with myoferlin (MYOF), a novel potential antitumor metastasis target, which regulates vesicle trafficking and metastasis-related proteins. Subsequent biophysical and biochemical methods verified that 6y bound to MYOF. Mechanism studies revealed that 6y inhibited pancreatic cancer metastasis through reversing the epithelial mesenchymal transition, inhibiting the secretions of matrix metalloproteinase and blocking the receptor tyrosine kinases. Our findings suggest that targeting MYOF with 6y may be a promising therapeutic strategy to prevent pancreatic cancer metastasis.