RESUMO
Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).
Assuntos
Fármacos Anti-HIV , HIV-1 , Produtos do Gene vif do Vírus da Imunodeficiência Humana , HIV-1/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Descoberta de Drogas , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Proteólise/efeitos dos fármacos , Simulação de Dinâmica MolecularRESUMO
Treatment of breast cancer has greatly evolved during the last decades, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is generally found in human breast cancer and other malignant tumors, and cyclin-dependent kinases (CDK) 4/6, a cell cycle-related regulatory nuclear protein, is deemed as an effective target for breast cancer treatment so far. Since DCAF16 E3 ligase is also mainly distributed in the nucleus, in this study, by combining Palbociclib and DCAF16 E3 ligase ligand KB02 with different linkers, a series of DCAF16 based CDK4/6 degraders were designed and synthesized. Among them, compound A4 showed potent inhibitory activity against CDK4/6, and decreased the level of CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Ciclo Celular , Divisão Celular , Quinase 4 Dependente de CiclinaRESUMO
Poly (ADP-ribose) polymerase (PARP) inhibitors show potent antiproliferative activity in treatment with triple-negative breast cancer (TNBC) when combined with chemotherapeutic drugs. However, the emergence of safety issues and drug-resistance of PARP inhibitors prompt us to search for new strategies. It was proved that Proteolysis Targeting Chimeras (PROTACs) is more effective than traditional small molecule which can induce target proteins degradation rather than inhibition. In this article, based on the Olaparib derivatives and cereblon (CRBN) E3 ligase ligands, a series of PARP1 degraders, with linkers bearing different length and type were designed and synthesized. Among them, compound LB23 showed efficacious antiproliferative activity in various human cancer cells and can induce PARP1 protein degradation effectively. Moreover, LB23 showed 60-fold degradation selectivity in tumor cells with low degradation toxicity in normal cells. This study shows that the PROTAC tumor selectivity can be optimized by tuning the length and composition of the linker.
Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Humanos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The crystal structure of viral infectivity factor (Vif) was reported recently, which makes it possible to design new inhibitors against Vif by structure-based drug design. Through analysis of the protein surface of Vif, the C2 pocket located in the N-terminal was found, which is suit for developing small molecular inhibitors. Then, in our article, fragment-based virtual screening (FBVS) was conducted and a series of fragments was obtained, among which, Zif-1 bearing indole scaffold and pyridine ring can form H-bonds with Tyr148 and Ile155. Subsequently, 19 derivatives of Zif-1 were synthesized. Through the immune-fluorescence staining and Western blot assays, Zif-15 shows potent activity in inhibiting Vif-mediated A3G degradation. Further docking experiment shows that Zif-15 form H-bond interactions with residues His139, Tyr148 and Ile155. Therefore, Zif-15 is a promising lead compound against Vif that can be used to treat AIDS.
Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , HIV-1/efeitos dos fármacos , Indóis/farmacologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Low-grade glioma (LGG) is heterogeneous at biological and transcriptomic levels, and it is still controversial for the definition and typing of LGG. Therefore, there is an urgent need for specific and practical molecular signatures for accurate diagnosis, individualized therapy, and prognostic evaluation of LGG. Cell death is essential for maintaining homeostasis, developing and preventing hyperproliferative malignancies. Based on diverse programmed cell death (PCD) related genes and prognostic characteristics of LGG, this study constructed a model to explore the mechanism and treatment strategies for LGG cell metastasis and invasion. We screened 1161 genes associated with PCD and divided 512 LGG samples into C1 and C2 subtypes by consistent cluster analysis. We analyzed the two subtypes' differentially expressed genes (DEGs) and performed functional enrichment analysis. Using R packages such as ESTIMATE, CIBERSOTR, and MCPcounter, we assessed immune cell scores for both subtypes. Compared with C1, the C2 subtype has a poor prognosis and a higher immune score, and patients in the C2 subtype are more strongly associated with tumor progression. LASSO and COX regression analysis screened four characteristic genes (CLU, FHL3, GIMAP2, and HVCN1). Using data sets from different platforms to validate the four-gene feature, we found that the expression and prognostic correlation of the four-gene feature had a high degree of stability, showing stable predictive effects. Besides, we found downregulation of CLU, FHL3, and GIMAP2 significantly impairs the growth, migration, and invasive potential of LGG cells. Take together, the four-gene feature constructed based on PCD-related genes provides valuable information for further study of the pathogenesis and clinical treatment of LGG.
Assuntos
Neoplasias Encefálicas , Regulação Neoplásica da Expressão Gênica , Glioma , Humanos , Glioma/genética , Glioma/patologia , Glioma/mortalidade , Glioma/diagnóstico , Prognóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Gradação de Tumores , Masculino , Feminino , Morte Celular/genética , TranscriptomaRESUMO
Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.
Assuntos
Quinase do Linfoma Anaplásico , Polietilenoglicóis , Proteólise , Animais , Humanos , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Proteólise/efeitos dos fármacos , Camundongos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Disponibilidade Biológica , Ensaios Antitumorais Modelo de Xenoenxerto , Micelas , Camundongos NusRESUMO
The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 µM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.
Assuntos
Antineoplásicos , Antígeno B7-H1 , Neoplasias da Mama , Proteólise , Proteólise/efeitos dos fármacos , Animais , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Humanos , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/síntese química , Acetamidas , PiridinasRESUMO
Combination of different molecular target inhibitors is an available method to improve the therapeutic effect on tumors. Herein, to achieve both tumor cell targeting and ALK degradation & CDK4/6 inhibition in one molecule, we designed and synthesized a novel GSH responsive "Y-PROTACs", Y5-3, a highly potent molecule with an IC50 value of 90 nM against H3122 cells, which can be cleaved into ALK PROTAC and CDK4/6 inhibitor moieties in tumor cells. Mechanism studies revealed that Y5-3 exert anti-tumor proliferation activity in vitro not only by ALK degradation and CDK4/6 inhibition, but also by ALK/CDK4 dual degradation. These properties make Y5-3 a GSH responsive multifunctional antitumor agent, and our work provide a new strategy for the development of multifunctional PROTACs.
Assuntos
Antineoplásicos , Neoplasias , Quimera de Direcionamento de Proteólise , Quinase do Linfoma Anaplásico , Proliferação de Células , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Proteólise , Neoplasias/tratamento farmacológicoRESUMO
Background: Activation of hepatic stellate cells (HSCs) is essential for the pathogenesis of liver fibrosis, there is no effective drug used to prevent or reverse the fibrotic process. Methods: With human hepatic stellate cell line LX-2 and mouse model of CCl4-induced liver fibrosis, we investigated the anti-fibrotic effect to liver fibrosis of extracellular vesicles (EVs) extracted from tea leaves through cytological tests such as cell proliferation, cell migration, and cell fibrotic marker. Results: It was found that tea-derived EVs (TEVs) inhibited HSCs activation. In CCl4-induced liver fibrosis model, TEVs treatment can significantly improve the pathological changes of liver tissue, inhibit collagen deposition, reduce the number of lipid droplets in liver tissue, and reduce serum AST and ALT levels. In addition, TEVs inhibited TGF-ß1 signaling and miR-44 in TEVs had the potential inhibitory effect on liver fibrosis. Conclusions: Taken together, our work suggesting that TEVs are novel therapeutic potential for liver fibrosis.
RESUMO
c-Myc is a transcription factor that is aberrantly expressed in the majority of human cancers. Recent studies unveiled that abnormal expression of c-Myc protein is involved in the development of colorectal cancer (CRC). Previously, we reported a novel phenoxy-N-phenylaniline derivative A-42 that can inhibit c-Myc protein and the growth of different CRC cancer cells potently. To look for a better candidate, the structure-activity relationship (SAR) of A ring, D ring and the linker between A and B rings of A-42 was investigated, and a series of compounds were synthesized. Among them, compound B13 was identified as the most active c-Myc inhibitor with cytotoxicity activity against HT29 and HCT116 cells at IC50 0.29 µM and IC50 0.64 µM, respectively, which is superior to that of A-42. According to the bioassays, compound B13 not only can suppress CRC cells proliferation and migration, but also inhibit the binding of c-Myc/Max dimer to DNA, which further interfere with the expression of the relevant proteins of apoptosis pathway. Furthermore, B13 could inhibit HT29 tumor growth in xenograft mouse models potently with tumor growth inhibitions (TGIs) up to 65.49% at dose of 40 mg/kg, which is superior to A-42 (55.82%, 40 mg/kg). Overall, B13 may potentially serve as an effective CRC therapy via blocking c-Myc/Max binding with DNA.
Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas c-myc , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas c-myc/genética , Proliferação de Células , Células HCT116 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , DNA/farmacologia , Linhagem Celular TumoralRESUMO
Triple negative breast cancer (TNBC) is a complex and heterogeneous neoplasm, and till now no effective therapies are available. PARP inhibitors, which target DNA repair, are lethal to those cells that have impaired homologous recombination (HR) pathway. So, PARP inhibitors might exert promising results in the treatment of BRCA-mutated TNBC, but show compromised effect to those wild-type TNBC. Herein, we describe a novel PROTACs C8, which was obtained by conjugating PARP1/2 inhibitor Olaparib to KB02, can induce potent and specific degradation of PARP2 by recruiting DCAF16 E3 ligase for treatment of wild-type TNBC. Moreover, C8 exhibits therapeutic potential in TNBC cell lines MDA-MB-231 both in vitro and in vivo. These studies demonstrated that the DCAF16 E3 ligases can be used in PARP2 PROTACs design, and C8, as a novel PARP2 selective DCAF16 based PROTACs, might be a promising lead compound for the treatment of BRCA-wild-type TNBC.
Assuntos
Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Mama Triplo Negativas , Ubiquitina-Proteína Ligases , Linhagem Celular Tumoral , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection is a serious public problem threatening global health. At present, although "cocktail therapy" has achieved significant clinical effects, HIV still cannot be completely eradicated. Furthermore, long-term antiviral treatment has caused problems such as toxic side effects, the emergence of drug-resistant viruses, and poor patient compliance. Therefore, it is highly necessary to continue to search for high-efficient, low-toxic anti-HIV drugs with new mechanisms. Natural products have the merits of diverse scaffolds, biological activities, and low toxicity that are deemed the important sources of drug discovery. Thus, finding lead compounds from natural products followed by structure optimization has become one of the important ways of modern drug discovery. Nowadays, many natural products have been found, such as berberine, gnidimacrin, betulone, and kuwanon-L, which exert effective anti-HIV activity through immune regulation, inhibition of related functional enzymes in HIV replication, and anti-oxidation. This paper reviewed these natural products, their related chemical structure optimization, and their anti-HIV mechanisms.
Assuntos
Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Produtos Biológicos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , HumanosRESUMO
Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Piperazinas/metabolismo , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/metabolismo , Piridinas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The viral infectivity factor (Vif)-apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) axis has been recognized as a valid target for developing novel small-molecule therapies for acquired immune deficiency syndrome (AIDS) or for enhancing innate immunity against viruses. Our previous work reported the novel Vif antagonist 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide (2) with strong antiviral activity. In this work, through optimizations of ring C of 2, we discovered the more potent compound 6m with an EC50 of 0.07 µM in non-permissive H9 cells, reflecting an approximately 5-fold enhancement of antiviral activity compared to that of 2. Western blotting indicated that 6m more strongly suppressed the defensive protein Vif than 2 at the same concentration. Furthermore, 6m suppressed the replication of various clinical drug-resistant HIV strains (FI, NRTI, NNRTI, IN and PI) with relatively high efficacy. These results suggested that compound 6m is a more potent candidate for treating AIDS.
Assuntos
Desaminase APOBEC-3G/metabolismo , Fármacos Anti-HIV/química , HIV-1/metabolismo , ortoaminobenzoatos/química , Produtos do Gene vif do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Sítios de Ligação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Farmacorresistência Viral/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , ortoaminobenzoatos/metabolismo , ortoaminobenzoatos/farmacologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismoRESUMO
BACKGROUND: Coumarin structures were widely employed in anti-cancer drug design. Herein we focused on the modifications of C4 and C6 positions on coumarin scaffold to get novel anti-cancer agents. OBJECTIVE: The objective of the current work was the synthesis and biological evaluation of a series of 4, 6-coumarin derivatives to get novel anticancer agents. METHODS: Thirty-seven coumarin derivatives were designed and synthesized, the antiproliferative activity of the compounds was evaluated against human cancer cell lines and non-cancerous cells by MTT assay. The bioactivities and underlying mechanisms of active molecules were studied and the ADMET characters were predicted. RESULTS: Among the compounds, 4-p-hydroxy phenol-6-pinacol borane coumarin (25) exhibited a promising anti- cancer activity to cancer cell lines in a dose-dependent manner and the toxicity to normal cells was low. The mechanism of action was observed by inducing G2/M phase arrest and apoptosis which was further confirmed via western blot. In silico ADMET prediction revealed that compound 25 is a drug-like small molecule with a favorable safety profile. CONCLUSION: The findings in this work may give vital information for further development of 6-pinacol borane coumarin derivatives as novel anti-cancer agents.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Desenho de Fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.
Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Células Tumorais CultivadasRESUMO
Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2'-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors.
Assuntos
Quinase do Linfoma Anaplásico/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cisteína/efeitos dos fármacos , Animais , Domínio Catalítico/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63â¯nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50â¯mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.
Assuntos
Antineoplásicos/farmacologia , Benzoxazinas/farmacologia , Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzoxazinas/administração & dosagem , Benzoxazinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC50 values against human cancer cell lines MV4-11, A375, and HeLa were 4.2, 7.1, and 11.6 µm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound-healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5.
Assuntos
Antineoplásicos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Área Sob a Curva , Sítios de Ligação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Proteínas Nucleares/metabolismo , Estrutura Terciária de Proteína , Curva ROC , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/metabolismoRESUMO
A series of novel 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-one derivatives were synthesized and their anti-cancer as well as cisplatin sensitization activities were evaluated. Among them, compounds 6e and 6h exhibited significant cisplatin sensitization activity against HCT116. Hoechst staining and annexin V-FITC/PI dual-labeling studies demonstrated that the combination of 6e/6h and cisplatin can induce tumour cell apoptosis. Western blot showed that the expression of ATR downstream protein, CHK1, decreased in 6e + cisplatin and 6h + cisplatin groups compared with that in the test compound and cisplatin group. Furthermore, docking of 6e/6h into the ATR structure active site revealed that the N1 and N8 atoms in the naphthyridine ring and the hybrid atom in the oxadiazole ring are involved in hydrogen bonding with Val170, Glu168 and Tyr155. Additionally, the naphthyridine ring is also involved in π-π stacking with Trp169. Accordingly, compounds 6e and 6h can be expected to be potential cisplatin sensitizers that can participate in HCT116 cancer therapy.