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1.
J Med Chem ; 63(6): 3327-3347, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32129996

RESUMO

Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/química , Quinase 9 Dependente de Ciclina/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade
2.
J Med Chem ; 63(6): 2986-3003, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32003560

RESUMO

Recently, our group identified that harmine is able to induce ß-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human ß-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human ß-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for ß-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.


Assuntos
Harmina/análogos & derivados , Harmina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Harmina/síntese química , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Ratos Wistar
3.
J Med Chem ; 63(6): 3028-3046, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32069401

RESUMO

PI3K-Akt-mTOR signaling pathway has been validated as an effective targeting pathway for cancer therapy. However, no PI3K/mTOR dual inhibitor has been approved by the FDA yet. Therefore, it is still essential to discover a candidate with good efficacy and low toxicity. In our design, a series of imidazo[1,2-a]pyridine derivatives had been synthesized and subjected to activity assessment in vitro and in vivo. 15a was proved to be a potent PI3K/mTOR dual inhibitor with excellent kinase selectivity, modest plasma clearance, and acceptable oral bioavailability. Besides, 15a displayed significant inhibition of tumor growth in HCT116 and HT-29 xenografts without obvious effect on body weight.


Assuntos
Imidazóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Desenho de Fármacos , Feminino , Células HCT116 , Células HT29 , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/metabolismo
4.
Alkaloids Chem Biol ; 83: 1-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32098648

RESUMO

Lamellarins are marine alkaloids containing fused 14-phenyl-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinoline or non-fused 3,4-diarylpyrrole-2-carboxylate ring systems. To date, more than 50 lamellarins have been isolated from a variety of marine organisms, such as mollusks, tunicates, and sponges. Many of them, especially fused type I lamellarins, exhibit impressive biological activity, such as potent cytotoxicity, topoisomerase I inhibition, protein kinases inhibition, and anti-HIV-1 activity. Due to their useful biological activity and limited availability from natural sources, a number of synthetic methods have been developed. In this chapter, we present an updated and comprehensive review on lamellarin alkaloids summarizing their isolation, synthesis, and biological activity.


Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/isolamento & purificação , Pirróis/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Pirróis/síntese química , Pirróis/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/isolamento & purificação
5.
J Med Chem ; 63(4): 1597-1611, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31977207

RESUMO

Herein we detail the discovery of a series of parthenolide dimers as activators of PKM2 and evaluation of their anti-GBM activities. The most promising compound 5 showed high potency to activate PKM2 with an AC50 value of 15 nM, inhibited proliferation and metastasis, and induced apoptosis of GBM cells. Compound 5 could promote tetramer formation of PKM2 and reduce nucleus translocation of PKM2 in GBM cells without influence on the expression of total PKM2, thereby inhibiting the STAT3 signal pathway in vitro and in vivo. PKM2 knockdown assay demonstrated that the anti-GBM effect of 5 mainly depended on the expression of PKM2 in vitro and in vivo. Compound 16, a prodrug of 5, markedly suppressed U118 tumor xenograft growth and reduced the weight of tumor. On the basis of these investigations, we propose that 16 might be considered as a promising lead compound for discovery of anti-GBM drugs.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piruvato Quinase/antagonistas & inibidores , Sesquiterpenos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Med Chem ; 63(4): 1624-1641, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31935084

RESUMO

SRC is a major regulator of many signaling pathways and contributes to cancer development. However, development of a selective SRC inhibitor has been challenging, and FDA-approved SRC inhibitors, dasatinib and bosutinib, are multitargeted kinase inhibitors. Here, we describe our efforts to develop a selective SRC covalent inhibitor by targeting cysteine 277 on the P-loop of SRC. Using a promiscuous covalent kinase inhibitor (CKI) SM1-71 as a starting point, we developed covalent inhibitor 15a, which discriminates SRC from other covalent targets of SM1-71 including TAK1 and FGFR1. As an irreversible covalent inhibitor, compound 15a exhibited sustained inhibition of SRC signaling both in vitro and in vivo. Moreover, 15a exhibited potent antiproliferative effects in nonsmall cell lung cancer cell lines harboring SRC activation, thus providing evidence that this approach may be promising for further drug development efforts.


Assuntos
Anilidas/farmacologia , Cisteína/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Domínio AAA , Sequência de Aminoácidos , Anilidas/síntese química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Quinases da Família src/química
7.
J Enzyme Inhib Med Chem ; 35(1): 574-583, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31994958

RESUMO

c-Jun N-terminal kinase (JNK) signalling regulates both cancer cell apoptosis and survival. Emerging evidence show that JNK promoted tumour progression is involved in various cancers, that include human pancreatic-, lung-, and breast cancer. The pro-survival JNK oncoprotein functions in a cell context- and cell type-specific manner to affect signal pathways that modulate tumour initiation, proliferation, and migration. JNK is therefore considered a potential oncogenic target for cancer therapy. Currently, designing effective and specific JNK inhibitors is an active area in the cancer treatment. Some ATP-competitive inhibitors of JNK, such as SP600125 and AS601245, are widely used in vitro; however, this type of inhibitor lacks specificity as they indiscriminately inhibit phosphorylation of all JNK substrates. Moreover, JNK has at least three isoforms with different functions in cancer development and identifying specific selective inhibitors is crucial for the development of targeted therapy in cancer. Some selective inhibitors of JNK are identified; however, their clinical studies in cancer are relatively less conducted. In this review, we first summarised the function of JNK signalling in cancer progression; there is a focus on the discussion of the novel selective JNK inhibitors as potential targeting therapy in cancer. Finally, we have offered a future perspective of the selective JNK inhibitors in the context of cancer therapies. We hope this review will help to further understand the role of JNK in cancer progression and provide insight into the design of novel selective JNK inhibitors in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos
8.
Eur J Med Chem ; 189: 112060, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31958738

RESUMO

A series of forty-six 5,6-annulated 2-arylthieno [2,3-d]pyrimidin-4(3H)-ones were prepared as potentially pleiotropic anticancer drugs with variance in the tubulin-binding trimethoxyphenyl motif at C-2 of a thieno [2,3-d]pyrimidine fragment, enlarged by additional rings of different size and substitution. By assessing their cytotoxicity against various cancer cells, their influence on the polymerization of neat tubulin and the dynamics of microtubule and F-actin cytoskeletons, and their vascular-disrupting and anti-angiogenic activities in vitro and in vivo, structure-activity relations were identified which suggest the 3-iodo-4,5-dimethoxyphenyl substituted thienopyrimidine 2e as a promising anticancer drug candidate for further research. 2020 Elsevier Ltd. All rights reserved.


Assuntos
Inibidores da Angiogênese/farmacologia , Pirimidinonas/farmacologia , Tiofenos/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Animais , Sítios de Ligação , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Galinhas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/metabolismo , Relação Estrutura-Atividade , Suínos , Tiofenos/síntese química , Tiofenos/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia , Peixe-Zebra
9.
J Med Chem ; 63(2): 621-637, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31910010

RESUMO

Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Humanos , Modelos Moleculares , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade
10.
J Med Chem ; 63(3): 1178-1198, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31895563

RESUMO

The sphingosine-1-phosphate (S1P) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of S1P has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis. While inhibitors of both SphKs have been reported, improvements in potency and selectivity are still needed. Toward that end, we performed structure-activity relationship profiling of 8 (SLM6031434) and discovered a heretofore unrecognized side cavity that increased inhibitor potency toward SphK2. Interrogating this region revealed that relatively small hydrophobic moieties are preferred, with 10 being the most potent SphK2-selective inhibitor (Ki = 89 nM, 73-fold SphK2-selective) with validated in vivo activity.


Assuntos
Amidinas/farmacologia , Oxidiazóis/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Amidinas/síntese química , Amidinas/metabolismo , Animais , Sítios de Ligação , Descoberta de Drogas , Humanos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Saccharomyces cerevisiae , Relação Estrutura-Atividade
11.
J Med Chem ; 63(3): 1216-1232, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31895569

RESUMO

Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed and approved by Food and Drug Administration for the treatment of non-small-cell lung cancers, but their efficacy can be compromised by acquired drug resistance conferred by EGFR-mutant variants. Here, we described the discovery of a novel E3 ligase von Hippel-Lindau-recruiting EGFR degrader, MS39 (compound 6), and a first-in-class E3 ligase cereblon-recruiting EGFR degrader, MS154 (compound 10), using the proteolysis targeting chimera technology. These compounds potently induced the degradation of mutant but not wild-type EGFR in an E3 ligase-dependent manner in cancer cell lines and effectively suppressed the growth of lung cancer cells compared with the corresponding negative controls. The global proteomic analyses revealed that the compounds were highly selective for EGFR. Furthermore, both compounds were bioavailable in mouse pharmacokinetic studies, and compound 6 is the first EGFR degrader suitable for in vivo efficacy studies. Overall, we provide a set of well-characterized chemical tools to the research community.


Assuntos
Gefitinibe/análogos & derivados , Gefitinibe/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe/metabolismo , Gefitinibe/farmacocinética , Humanos , Masculino , Camundongos , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Proteólise , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
12.
J Med Chem ; 63(3): 1397-1414, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31934767

RESUMO

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.


Assuntos
Alquinos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Alquinos/síntese química , Alquinos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade
13.
J Med Chem ; 63(3): 1313-1327, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31972088

RESUMO

Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barré syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 µM and displayed EC50 values of 1.52 µM and 1.91 µM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.


Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas/antagonistas & inibidores , Infecção por Zika virus/tratamento farmacológico , Animais , Antivirais/síntese química , Antivirais/metabolismo , Domínio Catalítico , Vírus da Dengue/efeitos dos fármacos , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas/química , Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Zika virus/efeitos dos fármacos
14.
J Med Chem ; 63(3): 1084-1104, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31895562

RESUMO

In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazolonas/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinonas/uso terapêutico , Quinuclidinas/uso terapêutico , Tiofenos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Formaldeído/química , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirazolonas/farmacologia , Pirimidinas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/metabolismo , Quinuclidinas/síntese química , Quinuclidinas/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Enzyme Inhib Med Chem ; 35(1): 468-477, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31902266

RESUMO

C-Met plays a crucial role in the development and progression of neoplastic disease. Type II c-Met inhibitors recognise the inactive DFG-out conformation of the kinase, result in better anti-tumour effects due to synergistic effect against the other kinases. According to our previous works, an (E)-N'-benzylidene group was selected as the initial fragment. Two series of (E)-N'-benzylidene hydrazides were designed by fragment growth method. The inhibitory activities were in vitro investigated against c-Met and VEGFR-2. Compound 10b exhibited the most potent inhibitory activity against the c-Met inhibitor (IC50 = 0.37 nM). Compound 11b exhibited multi-target c-Met kinase inhibitory activity as a potential type II c-Met inhibitor (IC50 = 3.41 nM against c-Met; 25.34 nM against VEGFR-2). The two compounds also demonstrate the feasibility of fragment-based virtual screening method for drug discovery.


Assuntos
Compostos de Benzilideno/síntese química , Compostos de Benzilideno/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Compostos de Benzilideno/química , Descoberta de Drogas , Humanos , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
16.
J Enzyme Inhib Med Chem ; 35(1): 555-564, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31967481

RESUMO

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 186: 111884, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761386

RESUMO

Mutation or abnormal expression of protein tyrosine kinases (PTKs) is one of the main causes of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, which have four subtypes including FGFR1, FGFR2, FGFR3 and FGFR4. Their abnormal expression in cells is considered to be the main cause of tumorigenesis, so inhibiting FGFRs is thought to be important targets for cancer treatment. This article mainly summarizes the recent development of FGFR inhibitors in the past 5 years, and hopes to guide the future research on the design and synthesis of FGFR inhibitors.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
18.
Eur J Med Chem ; 186: 111878, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757524

RESUMO

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Fígado/química , Fígado/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/síntese química , Piperazinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
19.
Eur J Med Chem ; 186: 111867, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757525

RESUMO

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 µM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 186: 111898, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31784186

RESUMO

Fangchinoline, a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, is known to exert anti-cancer activity. A series of new fangchinoline derivatives have been synthesized and evaluated for their anti-cancer activity. In cell viability assay, these fangchinoline derivatives displayed higher proliferation inhibitory activity on leukemia and breast cancer cell lines than the parental compound. Among them, 3e exhibited strongest cell growth inhibitory activity in a dose- and time-dependent manner on leukemia cell line HEL through induction of G0/G1 cell cycle arrest and apoptosis. Treatment of HEL cells with 3e also resulted in significant suppression of the MAPK and PI3K/AKT pathway as well as c-MYC downregulation, which may responsible for induction of apoptosis and cell cycle arrest. In docking analysis, high affinity interaction between 3e and Akt1 was responsible for drastic kinase inhibition by the compound. This derivative compound may be useful as a potent anti-cancer agent for treatment of leukemia.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzilisoquinolinas/síntese química , Benzilisoquinolinas/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , 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 , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
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