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1.
Cancer Biol Ther ; : 1-14, 2022 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-35000525

RESUMO

PARP1 and Chk1 inhibitors have been shown to be synergistic in different cancer models in relatively short time treatment modes. However, the consequences of long-term/repeated treatments with the combinations in cancer models remain unclear. In this study, the synergistic cytotoxicity of their combinations in 8 tumor cell lines was confirmed in a 7-day exposure mode. Then, pancreatic Capan-1 cells were repeatedly treated with the PARP1 inhibitor olaparib, the Chk1 inhibitor rabusertib or their combination for 211-214 days, during which the changes in drug sensitivity were monitored at a 35-day interval. Unexpectedly, among the 3 treatment modes, the combination treatments resulted in the highest-grade resistance to Chk1 (~14.6 fold) and PARP1 (~420.2 fold) inhibitors, respectively. Consistently, G2/M arrest and apoptosis decreased significantly in the resulting resistant variants exposed to olaparib. All 3 resistant variants also unexpectedly obtained enhanced migratory and invasive capabilities. Moreover, the combination treatments resulted in increased migration and invasion than olaparib alone. The expression of 124 genes changed significantly in all the resistant variants. We further demonstrate that activating CXCL3-ERK1/2 signaling might contribute to the enhanced migratory capabilities rather than the acquired drug resistance. Our findings indicate that repeated treatments with the rabusertib/olaparib combination result in increased drug resistance and a more aggressive cell phenotype than those with either single agent, providing new clues for future clinical anticancer tests of PARP1 and Chk1 inhibitor combinations.

3.
Signal Transduct Target Ther ; 6(1): 165, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895786

RESUMO

The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/metabolismo , Simulação por Computador , Reposicionamento de Medicamentos , Modelos Biológicos , SARS-CoV-2/metabolismo , Humanos
4.
J Med Chem ; 64(9): 6161-6178, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33857374

RESUMO

The ubiquitin-like protein NEDD8 is a critical signaling molecule implicated in the functional maintenance and homeostasis of cells. Dysregulation of this process is involved in a variety of human diseases, including cancer. Therefore, NEDD8-activating enzyme E1 (NAE), the only activation enzyme of the neddylation pathway, has been an emergent anticancer target. In view of the single-agent modest response of the clinical NAE inhibitor, pevonedistat (compound 1, MLN4924), efforts on development of new inhibitors with both high potency and better safety profiles are urgently needed. Here, we report a structural hopping strategy by optimizing the central deazapurine framework and the solvent interaction region of compound 1, leading to compound 26 bearing a pyrimidotriazole scaffold. Compound 26 not only has compatible potency in the biochemical and cell assays but also possesses improved pharmacokinetic (PK) properties than compound 1. In vivo, compound 26 showed significant antitumor efficacy and good safety in xenograft models.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Tirapazamina/química , Tirapazamina/farmacologia , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Cisplatino , Inibidores Enzimáticos/farmacocinética , Humanos , Ifosfamida , Mitomicina , Tirapazamina/farmacocinética , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Genomics ; 113(3): 1057-1069, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33667649

RESUMO

The Bromodomain and Extra-terminal domain (BET) proteins are promising targets in treating cancers. Although BET inhibitors have been in clinical trials, they are limited by lacking of suitable biomarkers to indicate drug responses in different cancers. Here we identify DHRS2, ETV4 and NOTUM as potential biomarkers to indicate drug resistance in liver cancer cells of a recently discovered BET inhibitor, Hjp-6-171. Furthermore, we confirm that reactivation of WNT pathway, the target of NOTUM, contributes to the drug sensitivity restoration in Hjp-6-171 resistant cells. Specially, combinations of Hjp-6-171 and a GSK3ß inhibitor CHIR-98014 show remarkable therapeutic effects in vitro and in vivo. Integrating RNA-seq and ChIP-seq data, we reveal the expression signature of ß-catenin regulated genes is contrary in sensitive cells to that in resistant cells. We propose WNT signaling molecules such as ß-catenin and ETV4 to be candidate biomarkers to indicate BET inhibitor responses in liver cancer patients.

6.
Invest New Drugs ; 39(5): 1213-1221, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33710464

RESUMO

G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.

7.
Biochem Pharmacol ; 185: 114435, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33539817

RESUMO

Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.


Assuntos
Antineoplásicos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Fatores Associados à Proteína de Ligação a TATA/antagonistas & inibidores , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Fator de Transcrição TFIID/antagonistas & inibidores , Fator de Transcrição TFIID/metabolismo , Células A549 , Animais , Relação Dose-Resposta a Droga , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Nus , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Cell Death Dis ; 12(2): 183, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589588

RESUMO

Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3ß and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3ß was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3ß could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Sinergismo Farmacológico , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HCT116 , Células HT29 , Células HeLa , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Distribuição Aleatória , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Nat Prod Bioprospect ; 11(1): 73-79, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33083968

RESUMO

A phytochemical investigation of the EtOH extract of the flowers of Lagerstroemia indica L. led to the isolation and characterization of a new pyrrole alkaloid, named lagerindicine (1), along with four known compounds (2-5). Their structures were elucidated by the detailed spectroscopic analysis and comparison with literature data, whereas the structure, in particularly, the absolute configuration (AC) of 1, was firmly determined by total synthesis. All the isolates were evaluated for their cytotoxic effects against human colon cancer cell (HCT-116), and compound 3 exhibited weak cytotoxicity with IC50 value of 28.4 µM.

10.
Bioorg Med Chem Lett ; 33: 127749, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340663

RESUMO

In an in-house screening, 1H-pyrrolo[2,3-b]pyridine scaffold was found to have high inhibition on TNIK. Several series of compounds were designed and synthesized, among which some compounds had potent TNIK inhibition with IC50 values lower than 1 nM. Some compounds showed concentration-dependent characteristics of IL-2 inhibition. These results provided new applications of TNIK inhibitors and new prospects of TNIK as a drug target.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 31: 127710, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33246105

RESUMO

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.


Assuntos
Antineoplásicos/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Piridazinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/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 , Humanos , Estrutura Molecular , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Piridazinas/síntese química , Piridazinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
12.
Nat Prod Res ; : 1-7, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33356576

RESUMO

A new diterpenoid with an unusual capnosane skeleton, sinuhumilol A (1), alone with twelve known diverse compounds (2-13), were isolated from the South China Sea soft coral Sinularia humilis. Their structures and stereochemistry were elucidated by extensive spectroscopic analysis, quantum chemical calculations, and/or by the comparison of the spectroscopic data with those reported in the literature. In bioassay, compound 11 exhibited interesting specific cytotoxicity against the human colon adenocarcinoma cell line HT-29 with IC50 value of 12.5 µM.

13.
Am J Cancer Res ; 10(9): 2813-2831, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042619

RESUMO

Several poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) have been approved for cancer therapy; however, intrinsic and acquired resistance has limited their efficacy in the clinic. In fact, cancer cells have developed multiple mechanisms to overcome PARPi cytotoxicity in even a single cancer cell. In this study, we generated three PARPi-resistant BRCA2-deficient pancreatic Capan-1 variant cells using olaparib (Capan-1/OP), talazoparib (Capan-1/TP), and simmiparib (Capan-1/SP). We identified novel mutations in intron 11 of BRCA2, which resulted in the expression of truncated BRCA2 splice isoforms. Functional studies revealed that only a fraction (32-49%) of PARPi sensitivity could be rescued by depletion of BRCA2 isoforms. In addition, the apoptosis signals (phosphatidylserine eversion, caspase 3/7/8/9 activation, and mitochondrial membrane potential loss) were almost completely abrogated in all PARPi-resistant variants. Consistently, overexpression of the anti-apoptotic proteins cyclooxygenase 2 (COX-2) and baculoviral IAP repeat-containing 3 (BIRC3) occurred in these variants. Depletion of COX-2 or BIRC3 significantly reduced apoptotic resistance in the PARPi-resistant sublines and reversed PARPi resistance by up to 70-72%. Furthermore, exogenous addition of prostaglandin E2, a major metabolic product of COX-2, inhibited PARPi-induced apoptotic signals; however, when combined with the BIRC3 inhibitor LCL161, there was significantly enhanced sensitivity of the resistant variants to PARPi. Finally, PARPi treatment or PARP1 depletion led to a marked increase in the mRNA and protein levels of COX-2 and BIRC3, indicating that PARP1 is a negative transcriptional regulator of these proteins. Together, our findings demonstrated that during the chronic treatment of cells with a PARPi, both BRCA2 intron 11 mutations and COX-2/BIRC3-mediated apoptotic resistance led to PARPi resistance in pancreatic Capan-1 cells.

14.
Bioorg Chem ; 103: 104223, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32891002

RESUMO

Seven new cembrane-type diterpenes, lobophytolins C-I (3-9), and one new prenylated-guiane-type diterpene, lobophytolin J (10), along with six known related ones (1, 2, 11-14), have been isolated from the soft coral Lobophytum sp. collected off the Xisha Island in the South China Sea. Their structures were elucidated by extensive spectroscopic analysis and quantum mechanical (QM)-NMR methods. The absolute configuration of lobophytolin H (8) was determined by the application of the modified Mosher's method and chemical transformation. Lobophytolin D (4) exhibited promising cytotoxicities in in vitro bioassays against HT-29, Capan-1, A549, and SNU-398 human cancer cell lines with IC50 values of 4.52, 6.62, 5.17, and 6.15 µM, respectively.


Assuntos
Antozoários/química , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/isolamento & purificação , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estereoisomerismo
15.
Steroids ; 161: 108681, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32590045

RESUMO

Two novel steroidal derivatives, erectsterates A (1) and B (2), a pair of epimers at C-10, were isolated from the South China Sea soft coral Sinularia erecta. Their structures were established by extensive spectroscopic analysis and deduction from biosynthesis route. Compounds 1 and 2 are rare steroids with a highly degradation in ring B and an ester linkage between A and C/D rings, similar with the known compounds chaxines B (3) and D from an edible mushroom Agrocybe chaxingu. To the best of our knowledge, this is the first report of such kind of steroid from soft coral. And a different biosynthetic route from the reported approach of chaxines was proposed in this paper. Interestingly, the ring C of 1 and 2 was formally oxidized by Baeyer-Villiger reaction to provide an unprecedented seven-membered lactone moiety in ring C of steroid. The in vitro anti-proliferative activities of 2 were evaluated against A549, HT-29, SNU-398 and Capan-1 cell lines. The results indicated that it showed weak cytotoxicity against the tested four cell lines.


Assuntos
Antozoários/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Esteroides/química , Esteroides/farmacologia , Animais , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Humanos , Estereoisomerismo , Esteroides/biossíntese
16.
Cell Death Dis ; 11(1): 71, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992690

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1) regulates gene transcription in addition to functioning as a DNA repair factor. Forkhead box O1 (FoxO1) is a transcription factor involved in extensive biological processes. Here, we report that PARP1 binds to two separate motifs on the FoxO1 promoter and represses its transcription in a polymerase-independent manner. Using PARP1-knock out (KO) cells, wild-type-PARP1-complemented cells and catalytic mutant PARP1E988K-reconstituted cells, we investigated transcriptional regulation by PARP1. PARP1 loss led to reduced DNA damage response and ~362-fold resistance to five PARP inhibitors (PARPis) in Ewing sarcoma cells. RNA sequencing showed 492 differentially expressed genes in a PARP1-KO subline, in which the FoxO1 mRNA levels increased up to more than five times. The change in the FoxO1 expression was confirmed at both mRNA and protein levels in different PARP1-KO and complemented cells. Moreover, exogenous PARP1 overexpression reduced the endogenous FoxO1 protein in RD-ES cells. Competitive EMSA and ChIP assays revealed that PARP1 specifically bound to the FoxO1 promoter. DNase I footprinting, mutation analyses, and DNA pulldown FREP assays showed that PARP1 bound to two particular nucleotide sequences separately located at -813 to -826 bp and -1805 to -1828 bp regions on the FoxO1 promoter. Either the PARPi olaparib or the PARP1 catalytic mutation (E988K) did not impair the repression of PARP1 on the FoxO1 expression. Exogenous FoxO1 overexpression did not impair cellular PARPi sensitivity. These findings demonstrate a new PARP1-gene promoter binding mode and a new transcriptional FoxO1 gene repressor.


Assuntos
Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Sarcoma de Ewing/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Dano ao DNA/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Técnicas de Inativação de Genes , Humanos , Mutação , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Regiões Promotoras Genéticas , Ligação Proteica , Sarcoma de Ewing/genética , Regulação para Cima
17.
Nat Prod Res ; 34(14): 1971-1976, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30721089

RESUMO

A new bis-γ-pyrone polypropionate, 4,16-di-epi-onchidiol (1), along with three known related compounds (2-4) were isolated from the marine pulmonate mollusk Onchidium sp. The structure of compound 1 was elucidated by extensive spectroscopic analysis and by comparison the NMR data with its stereoisomers 2-4, whereas its absolute configuration was determined by the combination of X-ray diffraction analysis and TDDFT-ECD calculation. In bioassay, the isolated compounds exhibited broad cytotoxicity against several cancer cell lines with IC50 values ranging from 24.6 to 88.5µM.


Assuntos
Antineoplásicos/isolamento & purificação , Moluscos/química , Pironas/isolamento & purificação , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Pironas/química , Estereoisomerismo
18.
Invest New Drugs ; 38(3): 700-713, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31267379

RESUMO

The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G0/G1 phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 µM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas/antagonistas & inibidores , Células A549 , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células PC-3 , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Med Chem ; 62(18): 8642-8663, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31490070

RESUMO

BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.


Assuntos
Desenho de Fármacos , Peptídeos/química , Proteínas/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Domínios Proteicos , Fatores de Transcrição/antagonistas & inibidores
20.
Molecules ; 24(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434258

RESUMO

Herein, a direct strategy to synthesize 3-(2-hydroxybenzoyl)-1-aza-anthraquinones with excellent efficiency, mild conditions, and benign functional group compatibility was reported. A variety of 3-formylchromone compounds were employed as compatible substrates and this protocol gave the 3-(2-hydroxybenzoyl)-1-aza-anthraquinone derivatives in good to excellent yields without inert gas and expensive transition metal catalysts. Some compounds displayed good anti-proliferative activities.


Assuntos
Antraquinonas/síntese química , Antineoplásicos/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Células HeLa , Humanos , Metais , Estrutura Molecular
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