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1.
Bioorg Med Chem Lett ; 91: 129381, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37336419

RESUMO

The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer was limited by the drug resistance caused by EGFRC797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFRC797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFRdel19/T790M/C797S) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFRdel19/T790M/C797S. Based on these results, A5 turned out to be effective reversible EGFRC797S-TKIs which can be further developed.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/química , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Resistencia a Medicamentos Antineoplásicos
2.
Bioorg Chem ; 140: 106815, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37672953

RESUMO

PI3Kδ inhibitors play an important role in the treatment of leukemia, lymphoma and autoimmune diseases. Herein, using our reported compounds as the lead compound, we designed and synthesized a series of selenium-containing PI3Kδ inhibitors based on quinazoline and pyrido[3,2-d]pyrimidine skeletons. Among them, compound Se15 showed sub-nanomolar inhibition against PI3Kδ and strong δ-selectivity. Moreover, Se15 showed potent anti-proliferative effect on SU-DHL-6 cells with an IC50 value of 0.16 µM. Molecular docking study showed that Se15 was able to form multiple hydrogen bonds with PI3Kδ and was close proximity and stacking with PI3Kδ selective region. In conclusion, the Se-containing compound Se15 bearing pyrido[3,2-d]pyrimidine scaffold is a novel potent and selective PI3Kδ inhibitor. The introduction of selenium can enrich the structure of PI3Kδ inhibitors and provide a new idea for design of novel PI3Kδ inhibitors.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Leucemia , Selênio , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia , Selênio/química , Selênio/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos
3.
Bioorg Chem ; 138: 106594, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37186998

RESUMO

The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and ß. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.


Assuntos
Aminoácidos , Inibidores de Proteínas Quinases , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Aminoácidos/farmacologia , Proliferação de Células
4.
Drug Dev Res ; 84(2): 337-394, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36606428

RESUMO

Recent years have witnessed the rapid development of targeted protein degradation (TPD), especially proteolysis targeting chimeras. These degraders have manifested many advantages over small molecule inhibitors. To date, a huge number of degraders have been excavated against over 70 disease-related targets. In particular, degraders against estrogen receptor and androgen receptor have crowded into phase II clinical trial. TPD technologies largely expand the scope of druggable targets, and provide powerful tools for addressing intractable problems that can not be tackled by traditional small molecule inhibitors. In this review, we mainly focus on the structures and biological activities of small molecule degraders as well as the elucidation of mechanisms of emerging TPD technologies. We also propose the challenges that exist in the TPD field at present.


Assuntos
Quimera de Direcionamento de Proteólise , Receptores de Estrogênio , Proteólise
5.
Drug Dev Res ; 84(8): 1709-1723, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37732677

RESUMO

The δ isoform of class I PI3K (PI3Kδ) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3Kδ (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 µM). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3Kδ, in concentration-dependent manner. In view of the significant improvement in potency of PI3Kδ and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3Kδ inhibitor.


Assuntos
Inibidores de Proteínas Quinases , Pirimidinas , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Proliferação de Células , Pirimidinas/farmacologia
6.
Bioorg Med Chem ; 66: 116803, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35561631

RESUMO

MicroRNA-21 is a carcinogenic microRNA, whose overexpression arises in a variety of tumor tissues. Hence, microRNA-21 a prospective target for cancer treatment, and regulation of microRNA-21 by small molecule inhibitors is deemed as a promising approach for tumor therapy. In this work, to discover potent microRNA-21 inhibitor, series of 4-(N-norfloxacin-acyl)aminobenzamides were designed and synthesized, and their inhibitory effects were appraised by utilizing dual luciferase reporter assays. The results indicated that compound A7 was the most efficient microRNA-21 small molecule inhibitor. What's more, A7 suppressed the migration of Hela cells and the colony formation of Hela and HCT-116 cells as well as promoted apoptosis of Hela cells. In the mechanism study, results of RT-qPCR certified that A7 could reduce the level of mature microRNA-21 via disrupting its expression at the transcriptional level of its primary form "pri-miR-21", which was distinct from most previous inhibitors directly binding with pre-miR-21. Noticeably, Western blotting and RT-qPCR uncovered A7 could upregulate the expression PTEN, EGR1 and SLIT2, which are the downstream functional targets of microRNA-21. These findings demonstrated that A7 was a promising microRNA-21 small molecule inhibitor and 4-(N-norfloxacin-acyl) aminobenzamide can serve as a new scaffold for discovery of potent microRNA-21 inhibitor.


Assuntos
Antineoplásicos , Benzamidas , MicroRNAs , Norfloxacino , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Proliferação de Células , Células HCT116 , Células HeLa , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Norfloxacino/farmacologia
7.
Bioorg Chem ; 128: 106057, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35964503

RESUMO

The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have accomplished impressive clinical achievements in the treatment of non-small-cell lung cancer (NSCLC). Nonetheless, the acquired drug resistance largely limits their clinical use. The tertiary C797S mutation in the kinase domain of EGFR is one of the major mechanisms responsible for the drug resistance. Therefore, much attention has been focused on the development of the fourth-generation EGFR-TKIs to target triple mutant epidermal growth factor receptor (EGFR) with C797S mutation. In this review, we outline the panorama of the fourth-generation EGFR-TKIs reported up to now with the attention paid on the design strategy, binding mode and antitumor activity of these EGFR-TKIs. We also discuss the challenges and prospects of the fourth-generation EGFR-TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/química
8.
Bioorg Chem ; 129: 106154, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36137311

RESUMO

Reactive oxygen species (ROS)-responsive prodrugs have received significant attention due to their capacity to target tumors to relieve the side effects caused by chemotherapy. Herein, a series of novel H2O2-activated theranostic prodrugs (CPTSe1-CPTSe7) were developed containing allyl phenyl selenide moieties as H2O2 acceptors. Compared with conventional boronate ester-based prodrug CPT-B, CPTSe1 was more stable in human plasma and showed a more complete release of camptothecin (CPT) in H2O2 inducing experiment. The selectively activated fluorescence signals of CPTSe1 in tumor cells make it useful for real-time monitoring of CPT release and H2O2 detection. Furthermore, excellent selectivity of CPTSe1 was achieved for tumor cells over normal cells. Our results provide a new platform for the development of H2O2-responsive theranostic prodrugs.


Assuntos
Pró-Fármacos , Humanos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio , Peróxido de Hidrogênio , Medicina de Precisão , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral
9.
Anticancer Drugs ; 32(4): 417-426, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33079732

RESUMO

The epidermal growth factor receptor (EGFR) signaling is frequently activated in lung cancer. In our previous study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-tyrosine kinase inhibitors to overcome acquired EGFR-T790M resistance. In this study, we selected the most promising compound Z25h to further investigate its effects and the underlying mechanism against non-small cell lung adenocarcinoma cells in vitro. Four different non-small cell lung adenocarcinoma cell lines were selected to test the antiviability profile of Z25h, and Hcc827 was the most sensitive to the drug treatment. Z25h caused cell cycle arrest at G0-G1 phase, and triggered strong early apoptosis in Hcc827 cells at 0.1 µM and late apoptosis in A549, H1975 and H1299 cells at 10 µM by 48 h treatment. Z25h inhibited the activation of EGFR and its downstream PI3K/AKT/mTOR pathway in the four tested cell lines, leading to the inhibition of cellular biosynthetic and metabolic processes and the promotion of apoptotic process. However, the effect of Z25h on mitogen-activated protein kinase pathway varies from cell lines. In addition, Z25h sensitized H1975 cells to X-ray radiation, and it also enhanced the radiation effect on A549 cells, while no obvious effect of Z25h was observed on the cell viability inhibition of H1299 cells induced by radiation. Hereby, Z25h might be considered as a potential therapeutic drug candidate for non-small cell lung adenocarcinoma treatment.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas/farmacologia , Células A549 , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia
10.
Invest New Drugs ; 38(5): 1218-1226, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823159

RESUMO

The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23 µM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Animais , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
11.
Bioorg Med Chem Lett ; 30(19): 127457, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32755681

RESUMO

PI3Kδ in B cells mediates antigen receptor signaling and promote neutrophil chemotaxis. The activation of PI3Kδ can cause mast cell maturation and degranulation, myeloid cell dysfunction, and cytokine release. As a key signal molecule, PI3Kδ interacts with the lipid binding domain of a variety of cellular proteins as a secondary messenger, ultimately affecting a series of significant cellular pathways in disease pathology. Therefore, many research organizations and pharmaceutical companies have studied it to develop effectively selective PI3Kδ inhibitors as therapeutics. This review summarizes research advances in varying chemical classes of selective PI3Kδ inhibitors and the structure-activity relationship, and it mainly focuses on the propeller- versus flat-type class of inhibitors.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Compostos Heterocíclicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Pneumopatias Obstrutivas/tratamento farmacológico , Estrutura Molecular , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
12.
Anticancer Drugs ; 30(9): 900-908, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30913062

RESUMO

Small-molecule targeted antitumor drugs are considered to be a promising treatment that can improve the efficacy and reduce side effects. PI3K/Akt signaling pathway is constantly activated in various cancers. We recently synthesized a series of novel compounds of PI3K/Akt pathway inhibitors and found the most effective analog to be W934. In this study, we explored the in-vitro and in-vivo antitumor effects of W934 on A549 non-small-cell lung cancer cells and HCT116 colorectal cancer cells. In-vitro assays showed that W934 caused an inhibition of PI3Kα kinase. W934 can significantly suppress the viability of A549 and HCT116 cells with IC50 values of 0.25 and 0.23 µmol/l, respectively. Besides, the inhibitory effects on cell migration, invasion and apoptosis were also observed after treatment of W934 for the indicated hours. According to the cell cycle analysis, W934 caused an inhibition of G0-G1 phase progression and correspondingly decreased the percentage of cells in S and G2-M phases. Results of western blotting indicated that W934 concentration dependently suppressed the activation of the PI3K/Akt pathway. Meanwhile, the in-vivo effect was studied in an A549 xenograft mouse model. Oral administration of W934 inhibited the tumor growth in a dose-dependent manner. Hereby, W934 might be considered as a potential therapeutic drug candidate for non-small-cell lung cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Células A549 , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
13.
J Org Chem ; 84(1): 463-471, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30540911

RESUMO

BF3·OEt2-mediated cross-coupling of (SnMe3)2 with aryl triazene offers a new strategy for the synthesis of aryl stannane. A variety of synthetically useful aryl trimethylstannanes were produced in moderate to good yields with this metal-free approach. One-pot sequential Stille cross-coupling with different aryl bromides provides a short entry to both symmetrical and unsymmetrical biaryl compounds.

14.
Bioorg Med Chem ; 27(19): 115035, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31434616

RESUMO

PI3Kδ is an intriguing target for developing anti-cancer agent. In this study, a new series of 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were synthesized. After biological evaluation, compounds A5 and A8 were identified as potent PI3Kδ inhibitors, with IC50 values of 1.3 and 0.7 nM, respectively, which are equivalent to or better than idelalisib (IC50 = 1.2 nM). Further PI3K isoforms selectivity evaluation showed that compound A5 afforded excellent PI3Kδ selectivity over PI3Kα, PI3Kß and PI3Kγ. A8 exhibited superior PI3Kδ/γ selectivity over PI3Kα and PI3Kß. Moreover, compounds A5 and A8 selectively exhibited anti-proliferation against SU-DHL-6 in vitro with IC50 values of 0.16 and 0.12 µM. Western blot analysis indicated that A8 could attenuate the AKTS473 phosphorylation. Molecular docking study suggested that A8 formed three key H-bonds action with PI3Kδ, which may account for its potent inhibition of PI3Kδ. These findings indicate that 4-(piperid-3-yl)amino substituted 6-pyridylquinazoline derivatives were potent PI3Kδ inhibitors with distinctive PI3K-isoforms and anti-proliferation profiles.


Assuntos
Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Quinazolinas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem ; 27(20): 114930, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176568

RESUMO

Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC50 = 4.5 nM), PI3Kß (IC50 = 4.5 nM), PI3Kγ (IC50 = 4.5 nM), PI3Kδ (IC50 = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC50 values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKTS473 in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.


Assuntos
Antineoplásicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Quinazolinas/farmacologia , Sulfonamidas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/química , Quinazolinas/administração & dosagem , Quinazolinas/química , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/química , Células Tumorais Cultivadas
16.
Biotechnol Appl Biochem ; 66(5): 755-762, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31021480

RESUMO

The therapeutic potential of microRNA-21 (miR-21) small-molecule inhibitors has been of particular interest to medicinal chemists. Moreover, the development of more facile screening methods is lacking. In the present study, two potential screening strategies for miR-21 small-molecule inhibitor including the stem-loop reverse transcription-quantitative PCR and dual luciferase reporter assay system were demonstrated and discussed in detail. A pmirGLO-miR21cswt plasmid and its two different mutants were constructed for dual luciferase reporter assay system. In addition, the sensitivity and specificity of these two methods were validated. Our results demonstrated that both strategies are decent choices for the screening of small-molecule inhibitors for miR-21 and possibly other miRNAs. Eventually, we applied our optimized strategy to discover and characterize several promising compounds such as azobenzene derivate A, enoxacin, and norfloxacin for their potential impact on intracellular miR-21 concentration.


Assuntos
Genes Reporter/efeitos dos fármacos , Luciferases de Vaga-Lume/antagonistas & inibidores , MicroRNAs/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Bibliotecas de Moléculas Pequenas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Genes Reporter/genética , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Luciferases de Vaga-Lume/genética , Luciferases de Vaga-Lume/metabolismo , Células Tumorais Cultivadas
17.
Bioorg Med Chem ; 26(12): 3619-3633, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29853340

RESUMO

In the present study, a new class of compounds containing pyrido[3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025 µM and 0.49 µM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50 = 1.7 nM) and EGFRL858R/T790M (IC50 = 23.3 nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50 mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.


Assuntos
Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Bioorg Med Chem ; 26(8): 2028-2040, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29534936

RESUMO

In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kß, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kδ pocket, which might explain their potent PI3Kδ inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3Kδ inhibitors.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinazolinas/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Purinas/química , Purinas/metabolismo , Purinas/farmacologia , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Quinazolinonas/química , Quinazolinonas/metabolismo , Quinazolinonas/farmacologia , Ratos , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 26(8): 2173-2185, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29576272

RESUMO

In present study, we described the synthesis and biological evaluation of a new class of EGFR inhibitors containing 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine scaffold. Thirty-one compounds were synthesized. Among them, compound C9 displayed the IC50 of 29.4 nM against HCC827 cell line and 1.9 nM against EGFRL858R. Compound C12 showed moderate inhibitory activity against EGFRL858R/T790M/C797S (IC50 = 114 nM). Western bolt assay suggested that compound C9 significantly inhibited EGFR phosphorylation. In vivo test, compound C9 remarkably exhibited inhibitory effect on tumor growth at 5.0 mg/kg by oral administration in established nude mouse HCC827 xenograft model. These results indicate that the 2,9-disubstituted 8-phenylsulfinyl/phenylsulfinyl-9H-purine derivatives can act as potent EGFR(L858R) inhibitors and effective anticancer agents. Additionally, optimization of compound C12 may result in discovering the fourth-generation EGFR-TKIs.


Assuntos
Antineoplásicos/síntese química , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Purinas/química , Administração Oral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Purinas/farmacologia , Purinas/uso terapêutico , Relação Estrutura-Atividade , Transplante Heterólogo
20.
J Enzyme Inhib Med Chem ; 33(1): 651-656, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29536777

RESUMO

Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC50) values of 4.5, 3.0, and 3.9 nM, respectively, which were comparable to idelalisib (IC50 = 2.7 nM). The further PI3K isoforms selectivity evaluation showed that compounds 12d, 14b and 14c have excellent PI3Kδ selectivity over PI3Kα, PI3Kß, and PI3Kγ. Moreover, compounds 12d, 14b and 14c also displayed different anti-proliferative profiles against a panel of four human B cell lines including Ramos, Raji, RPMI-8226, and SU-DHL-6. The molecular docking simulation indicated several key hydrogen bonding interactions were formed. This study suggests the introduction of pyrrolidineoxy or piperidineamino groups into the 4-position of quinazoline leads to new potent and selective PI3Kδ inhibitors.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/farmacologia , Quinazolinas/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirrolidinas/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
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