RESUMO
Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-driven connective tissue disorder that results in fibrosis of the skin and internal organs such as the lung. Fibroblasts are known as the main effector cells involved in the progression of SSc through the induction of extracellular matrix (ECM) proteins and myofibroblast differentiation. Here, we demonstrate that 4'-(cyclopropylmethyl)-N2-4-pyridinyl-[4,5'-bipyrimidine]-2,2'-diamine (PIK-III), known as class III phosphatidylinositol 3-kinase (PIK3C3/VPS34) inhibitor, exerts potent antifibrotic effects in human dermal fibroblasts (HDFs) by attenuating transforming growth factor-beta 1 (TGF-ß1)-induced ECM expression, cell contraction and myofibroblast differentiation. Unexpectedly, neither genetic silencing of PIK3C3 nor other PIK3C3 inhibitors (e.g., SAR405 and Autophinib) were able to mimic PIK-III-mediated antifibrotic effect in dermal fibroblasts, suggesting that PIK-III inhibits fibroblast activation through another signaling pathway. We identified that PIK-III effectively inhibits p38 activation in TGF-ß1-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.
Assuntos
Fibroblastos , Fibrose , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/genética , Bleomicina , Fator de Crescimento Transformador beta1/metabolismo , Pirimidinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Piridinas/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pele/patologia , Pele/metabolismo , Pele/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismoRESUMO
The combination of gemcitabine, PI3K-Akt pathway inhibitors, and radiation in human glioma cell lines shows potential to enhance radiation sensitivity in aggressive brain tumors. Inhibiting the overactive PI3K-Akt pathway may increase tumor vulnerability to treatment. However, variability in responses among different glioma cell lines highlights the need for personalized approaches. Future research should focus on identifying biomarkers to tailor treatment for individual patients. Additionally, addressing safety concerns and the challenges of translating preclinical findings into clinical practice is crucial. Further studies should explore the therapy's molecular mechanisms and evaluate its clinical potential.
Assuntos
Neoplasias Encefálicas , Desoxicitidina , Gencitabina , Glioma , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/radioterapia , Glioma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Purpose: Sangbaipi decoction (SBPD), a traditional Chinese medicine (TCM) prescription, has been widely used to treat acute exacerbation of chronic obstructive pulmonary disease (AECOPD), while the underlying pharmacological mechanism remains unclear due to the complexity of composition. Methods: A TCM-active ingredient-drug target network of SBPD was constructed utilizing the TCM-Systems-Pharmacology database. AECOPD-relevant proteins were gathered from Gene Cards and the Online-Mendelian-Inheritance-in-Man database. Protein-protein interaction, GO and KEGG enrichment analyses of the targets from the intersection of SBPD and AECOPD targets were performed to identify the core signaling pathway, followed by molecular docking verification of its interaction with active ingredients. The network pharmacology results were checked using in-vivo experiments. To induce AECOPD, rats were exposure to combined tobacco smoke and lipopolysaccharide (LPS). Then rats underwent gavage with stigmasterol (SM) after successful modeling. The involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was investigated using its inhibitor, LY294002. Lung function and histopathology were examined. The levels of inflammatory cytokines in the lung and serum were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot and/or Enzyme-linked immunosorbent assay (ELISA). Results: SM was recognized as an active ingredient of SBPD and stably bound to Akt1. SM improved lung function and histological abnormalities, concomitant with suppressed PI3K/Akt signaling, downregulated lung and serum Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) levels and serum transforming growth factor-ß (TGF-ß) levels and upregulated lung and serum Interleukin 10 (IL-10) levels in AECOPD rats. In AECOPD rats, LY294002 restored lung function, and it also improved lung histological abnormalities and inflammation, which was found to be potentiated by SM. Conclusion: SM targets PI3K/Akt signaling to reduce lung injury and inflammation in AECOPD rats.
Assuntos
Medicamentos de Ervas Chinesas , Pulmão , Farmacologia em Rede , Fosfatidilinositol 3-Quinase , Proteínas Proto-Oncogênicas c-akt , Doença Pulmonar Obstrutiva Crônica , Estigmasterol , Animais , Masculino , Ratos , Anti-Inflamatórios/farmacologia , Cromonas/farmacologia , Citocinas/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Progressão da Doença , Medicamentos de Ervas Chinesas/farmacologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Estigmasterol/farmacologiaRESUMO
The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A selective PI3Kα inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a novel series of selective PI3Kα inhibitors using structure-based drug design and molecular docking to inform the design of 6H-benzo[c]chromen inhibitors. XJTU-L453 (21) was identified with PI3Kα inhibitory potency and unique selectivity over other PI3K isoforms and all other kinases tested. Further evaluation of pharmacokinetic properties and in vivo efficacy led to the identification of the preclinical potential of XJTU-L453 (21).
Assuntos
Desenho de Fármacos , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase , Animais , Humanos , Camundongos , Ratos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologiaRESUMO
PI3Kγ and PI3Kδ plays critical roles in exerting immunosuppression by targeting regulatory T cells and myeloid cells. Dual inhibition of PI3Kγ and PI3Kδ has emerged as a novel therapeutic strategy for cancer immunotherapy. We herein report a series of pyrazolopyridine derivatives with distinct scaffolds as potent and selective dual inhibitors of PI3Kγ and PI3Kδ. Among them, 20e (IHMT-PI3K-315) displays an IC50 value of 4.0 and 9.1 nM against PI3Kγ and PI3Kδ respectively in biochemical assays. Meanwhile, it potently inhibits PI3Kγ and PI3Kδ-mediated phosphorylation of AKT S473 with EC50 values of 0.028 and 0.013 µM in cellular assays. In addition, 20e exhibits a favorable selectivity profile in protein kinases at 1 µM. In bone marrow-derived macrophages (BMDM), 20e can repolarize the M2 phenotype to the M1 phenotype. In vivo, 20e demonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Classe Ib de Fosfatidilinositol 3-Quinase , Inibidores de Fosfoinositídeo-3 Quinase , Pirazóis , Piridinas , Animais , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Piridinas/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Pirazóis/farmacologia , Pirazóis/química , Pirazóis/síntese química , Pirazóis/farmacocinética , Humanos , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Camundongos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Descoberta de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos Endogâmicos C57BL , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Simulação de Acoplamento MolecularRESUMO
Aberrant activation or mutation of the EGFR-PI3K-Akt-mTOR signaling pathway has been implicated in a wide range of human cancers, especially non-small-cell lung cancer (NSCLC). Thus, dual inhibition of EGFR and PI3K has been investigated as a promising strategy to address acquired drug resistance resulting from the use of tyrosine kinase inhibitors. A series of dual EGFR/PI3Kα inhibitors was synthesized using pharmacophore hybridization of the third-generation EGFR inhibitor olmutinib and the PI3Kα selective inhibitor TAK-117. The optimal compound 30k showed potent kinase inhibitory activities with IC50 values of 3.6 and 30.0 nM against EGFRL858R/T790M and PI3Kα, respectively. Compound 30k exhibited a significant antiproliferative effect in NCI-H1975 cells with a higher selectivity profile than olmutinib. The potential antitumor mechanism, molecular binding modes, and in vitro metabolic stability of compound 30k were also clarified.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Simulação de Acoplamento MolecularRESUMO
PI3K inhibitors have emerged as promising therapeutic agents due to their critical role in various cellular processes, particularly in cancer, where the PI3K pathway is frequently dysregulated. This review explores the evolutionary path of PI3K inhibitors from laboratory discovery to clinical application. The journey begins with early laboratory investigations into PI3K signaling and inhibitor development, highlighting fundamental discoveries that laid the foundation for subsequent advancements. Optimization strategies, including medicinal chemistry approaches and structural modifications, are scrutinized for their contributions to enhancing inhibitor potency, selectivity, and pharmacokinetic properties. The translation from preclinical studies to clinical trials is examined, emphasizing pivotal trials that evaluated efficacy and safety profiles. Challenges encountered during clinical development are critically assessed. Finally, the review discusses ongoing research directions and prospects for PI3K inhibitors, underscoring these agents' continuous evolution and therapeutic potential.
Assuntos
Descoberta de Drogas , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Humanos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.
Assuntos
Fibroblastos , Glucosilceramidase , Doenças por Armazenamento dos Lisossomos , Lisossomos , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Glucosilceramidase/metabolismo , Glucosilceramidase/genética , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/genética , Doença de Gaucher/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologiaAssuntos
Antineoplásicos , Receptores ErbB , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences tumour progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), contribute to immune suppression in the TME (Nakamura and Smyth in Cell Mol Immunol 17(1):1-12 (2020). https://doi.org/10.1038/s41423-019-0306-1 ; DeNardo and Ruffell in Nat Rev Immunol 19(6):369-382 (2019). https://doi.org/10.1038/s41577-019-0127-6 ). This poses a significant challenge for novel immunotherapeutics that rely on host immunity to exert their effect. This systematic review explores the preclinical evidence surrounding the inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) as a strategy to reverse myeloid-driven immune suppression in solid tumours. EMBASE, MEDLINE, and PubMed databases were searched on 6 October 2022 using keyword and subject heading terms to capture relevant studies. The studies, focusing on PI3Kγ inhibition in animal models, were subjected to predefined inclusion and exclusion criteria. Extracted data included tumour growth kinetics, survival endpoints, and immunological responses which were meta-analysed. PRISMA and MOOSE guidelines were followed. A total of 36 studies covering 73 animal models were included in the review and meta-analysis. Tumour models covered breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head and neck, soft tissue, gastric, and oral cancer. The predominant PI3Kγ inhibitors were IPI-549 and TG100-115, demonstrating favourable specificity for the gamma isoform. Combination therapies, often involving chemotherapy, radiotherapy, immune checkpoint inhibitors, biological agents, or vaccines, were explored in 81% of studies. Analysis of tumour growth kinetics revealed a statistically significant though heterogeneous response to PI3Kγ monotherapy, whereas the tumour growth in combination treated groups were more consistently reduced. Survival analysis showed a pronounced increase in median overall survival with combination therapy. This systematic review provides a comprehensive analysis of preclinical studies investigating PI3Kγ inhibition in myeloid-driven tumour immune suppression. The identified studies underscore the potential of PI3Kγ inhibition in reshaping the TME by modulating myeloid cell functions. The combination of PI3Kγ inhibition with other therapeutic modalities demonstrated enhanced antitumour effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3Kγ-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types.
Assuntos
Neoplasias , Microambiente Tumoral , Humanos , Animais , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Microambiente Tumoral/imunologia , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Imunoterapia/métodos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêuticoRESUMO
Background: BMS-1166, a PD-1/PD-L1 inhibitor, inhibits the binding of PD-L1 to PD-1, restores T cell function, and enhances tumor immune response. However, mutations in the tumor suppressor or impaired cellular signaling pathways may also lead to cellular transformation. In this study, the SW480 and SW480R cell lines were used as the model to elucidate the treatment with BMS-1166, BEZ235, and their combination. Methods: MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis were analyzed by flow cytometry. The phosphorylation level of the key kinases in the PI3K/Akt/mTOR and MAPK pathways, PD-L1, and the protein levels related to the proliferation, migration, and apoptosis were assessed using western blotting. Results: BEZ235 enhanced BMS-1166-mediated cell proliferation and migration inhibition in SW480 and SW480R cells and promoted apoptosis. Interestingly, the downregulation of the negative regulator PTEN raised the PD-L1 level, which was abolished by the inhibition of Akt. BMS-1166 promoted PI3K, Akt, mTOR, and Erk phosphorylation. However, the combination of BEZ235 with BMS-1166 suppressed the expression of PI3K, p-Akt, p-mTOR, and p-Erk in SW480 and SW480R cells compared to BMS-1166 or BEZ235 single treatment by inhibiting the binding of PD1 to PD-L1. Conclusions: PD-1 binds to PD-L1 and activates the PI3K/mTOR and MAPK pathways, which might be the molecular mechanism of acquired resistance of CRC to BMS-1166. The combination of the two drugs inhibited the phosphorylation of PI3K, Akt, and Erk in the PI3K/mTOR and MAPK pathway, i.e., BEZ235 enhanced the BMS-1166 treatment effect by blocking the PI3K/mTOR pathway and interfering with the crosstalk of the MAPK pathway. Therefore, these findings provide a theoretical basis for BMS-1166 combined with BEZ235 in the trial treatment of colorectal cancer.
Assuntos
Apoptose , Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Imidazóis , Inibidores de Fosfoinositídeo-3 Quinase , Quinolinas , Serina-Treonina Quinases TOR , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Sinergismo Farmacológico , Imidazóis/farmacologia , Inibidores de MTOR/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family.
Assuntos
Antineoplásicos , Terapia de Alvo Molecular , Neoplasias , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Animais , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer.
Assuntos
Metiltransferases , Proteínas Ribossômicas , Ribossomos , Neoplasias Gástricas , Animais , Feminino , Humanos , Camundongos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Lisina/metabolismo , Metilação/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Metiltransferases/deficiência , Metiltransferases/metabolismo , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Biossíntese de Proteínas , Proteínas Ribossômicas/química , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lymphoma, a blood tumor, has become the ninth most common cancer in the world in 2020. Targeted inhibition is one of the important treatments for lymphoma. At present, there are many kinds of targeted drugs for the treatment of lymphoma. Studies have shown that Histone deacetylase, Bruton's tyrosine kinase and phosphoinositide 3-kinase all play an important role in the occurrence and development of tumors and become important and promising inhibitory targets. This article mainly expounds the important role of these target protein in tumors, and introduces the mechanism of action, structure-activity relationship and clinical research of listed small molecule inhibitors of these targets, hoping to provide new ideas for the treatment of lymphoma.
[Box: see text].
Assuntos
Tirosina Quinase da Agamaglobulinemia , Antineoplásicos , Linfoma , Bibliotecas de Moléculas Pequenas , Humanos , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Linfoma/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Histona Desacetilases/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Relação Estrutura-Atividade , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Terapia de Alvo MolecularAssuntos
Classe Ib de Fosfatidilinositol 3-Quinase , Leucemia Mieloide Aguda , Leucemia Mieloide Aguda/genética , Humanos , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Animais , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Inibidores de Proteínas Quinases , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Linhagem Celular Tumoral , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológicoRESUMO
Metastatic recurrence is still a major challenge in breast cancer treatment. Patients with triple negative breast cancer (TNBC) develop early recurrence and relapse more frequently. Due to the lack of specific therapeutic targets, new targeted therapies for TNBC are urgently needed. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is one of the active pathways involved in chemoresistance and survival of TNBC, being considered as a potential target for TNBC treatment. Our present study identified ticagrelor, an anti-platelet drug, as a pan-PI3K inhibitor with potent inhibitory activity against four isoforms of class I PI3K. At doses normally used in clinic, ticagrelor showed weak cytotoxicity against a panel of breast cancer cells, but significantly inhibited the migration, invasion and the actin cytoskeleton organization of human TNBC MDA-MB-231 and SUM-159PT cells. Mechanistically, ticagrelor effectively inhibited PI3K downstream mTOR complex 1 (mTORC1) and mTORC2 signaling by targeting PI3K and decreased the protein expression of epithelial-mesenchymal transition (EMT) markers. In vivo, ticagrelor significantly suppressed tumor cells lung metastasis in 4T1 tumor bearing BALB/c mice model and experimental lung metastasis model which was established by tail vein injection of GFP-labeled MDA-MB-231 cells. The above data demonstrated that ticagrelor can inhibit the migration and invasion of TNBC both in vitro and in vivo by targeting PI3K, suggesting that ticagrelor, a pan-PI3K inhibitor, might represent a promising therapeutic agent for the treatment of metastatic TNBC.
Assuntos
Camundongos Endogâmicos BALB C , Ticagrelor , Neoplasias de Mama Triplo Negativas , Ticagrelor/farmacologia , Ticagrelor/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Humanos , Feminino , Camundongos , Linhagem Celular Tumoral , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Movimento Celular/efeitos dos fármacos , Metástase NeoplásicaRESUMO
YM201636 is the potent PIKfyve inhibitor that is being actively investigated for liver cancer efficacy. In this study, computer simulations and experiments were conducted to investigate the interaction mechanism between YM201636 and the transport protein HSA. Results indicated that YM201636 is stably bound between the subdomains IIA and IIIA of HSA, supported by site marker displacement experiments. YM201636 quenched the endogenous fluorescence of HSA by static quenching since a decrease in quenching constants was observed from 7.74 to 2.39 × 104 M-1. UV-vis and time-resolved fluorescence spectroscopy confirmed the YM201636-HSA complex formation and this binding followed a static mechanism. Thermodynamic parameters ΔG, ΔH, and ΔS obtained negative values suggesting the binding was a spontaneous process driven by Van der Waals interactions and hydrogen binding. Binding constants ranged between 5.71 and 0.33 × 104 M-1, which demonstrated a moderately strong affinity of YM201636 to HSA. CD, synchronous, and 3D fluorescence spectroscopy revealed that YM201636 showed a slight change in secondary structure. The increase of Kapp and a decrease of PSH with YM201636 addition showed that YM201636 changed the surface hydrophobicity of HSA. The research provides reasonable models helping us further understand the transportation and distribution of YM201636 when it absorbs into the blood circulatory system.
Assuntos
Albumina Sérica Humana , Espectrometria de Fluorescência , Humanos , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Termodinâmica , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/química , Modelos Moleculares , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Pirimidinas/químicaRESUMO
The goal of cancer research is to identify characteristics of cancer cells that allow them to be selectively eliminated without harming the host. One such characteristic is autophagy dependence. Cancer cells survive, proliferate, and metastasize under conditions where normal cells do not. Thus, the requirement in cancer cells for more energy and macromolecular biosynthesis can evolve into a dependence on autophagy for recycling cellular components. Recent studies have revealed that autophagy, as well as different forms of cellular trafficking, is regulated by five phosphoinositides associated with eukaryotic cellular membranes and that the enzymes that synthesize them are prime targets for cancer therapy. For example, PIKFYVE inhibitors rapidly disrupt lysosome homeostasis and suppress proliferation in all cells. However, these inhibitors selectively terminate PIKFYVE-dependent cancer cells and cancer stem cells with not having adverse effect on normal cells. Here, we describe the biochemical distinctions between PIKFYVE-sensitive and -insensitive cells, categorize PIKFYVE inhibitors into four groups that differ in chemical structure, target specificity and efficacy on cancer cells and normal cells, identify the mechanisms by which they selectively terminate autophagy-dependent cancer cells, note their paradoxical effects in cancer immunotherapy, and describe their therapeutic applications against cancers.
Assuntos
Autofagia , Neoplasias , Autofagia/efeitos dos fármacos , Humanos , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêuticoRESUMO
Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.