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1.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500603

RESUMO

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.


Assuntos
Aurora Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
2.
Eur J Med Chem ; 221: 113495, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34020340

RESUMO

Aurora kinases are a family of serine/threonine kinases that play a crucial role in cell proliferation through the regulation of mitotic spindles. These kinases are the regulatory proteins localized in the various phases of the cell cycle and are involved in centrosome maturation, chromosome alignment, chromosomal segregation, and cytokinesis. They have emerged as one of the validated drug targets for anticancer drug discovery as their overexpression has been implicated in the pathogenesis of various carcinomas. Inhibitors of Aurora kinases induce growth inhibition and apoptosis in a variety of tumor cells. Hence, the design and development of Aurora kinase inhibitors have been widely explored in recent years by the scientific community as potential anticancer agents. Various Aurora kinase inhibitors have been under preclinical and clinical investigations as antitumor agents. This review summarizes the recent strategies of various researchers for the design and development of Aurora kinase inhibitors belonging to different structural classes. Their bioactivity, SARs, molecular modelling, and mechanistic studies have also been described. The comprehensive compilation of research work carried out in the field will provide inevitable scope for the design and development of novel drug candidates with better selectivity and efficacy. The review is constructed after the exhaustive research in this discipline and includes the papers from 2011 to 2020.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Aurora Quinases/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
3.
Expert Opin Ther Pat ; 31(7): 625-644, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33573401

RESUMO

Introduction: Aurora kinases are a family of serine/threonine kinases, and promote mitotic spindle assembly by regulating centrosome duplication and separation. Aurora kinases are overexpressed in a variety of tumor cell lines, thus, the use of Aurora kinase small-molecule inhibitors has become a potential treatment option for cancer.Areas covered: As a continuing review of Aurora kinase inhibitors and their patents published in 2009, 2011 and 2014. Herein, we updated the information for Aurora kinase inhibitors in clinical trials and the patents filed from 2014 to 2020. PubMed, Scopus, SciFinder, and www.clinicaltrials.gov databases were used for searching the clinical information and patents of Aurora kinase inhibitors.Expert opinion: Even though Aurora A or B selective as well as pan inhibitors show preclinical and clinical efficacy, so far, no Aurora kinase inhibitor has been approved for clinical use. Preliminary evidence suggested that highly selective Aurora kinase or multi-target inhibitors as a single agent as well as in combination therapy are still the current main development trend of Aurora kinase inhibitors.


Assuntos
Aurora Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Aurora Quinases/metabolismo , Linhagem Celular Tumoral , Desenvolvimento de Medicamentos , Humanos , Neoplasias/enzimologia , Patentes como Assunto
4.
EBioMedicine ; 64: 103220, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33529999

RESUMO

BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR), and downstream pathway activation appears to be a common oncogenic driver in the majority of head and neck squamous cell cancers (HNSCCs); yet targeting EGFR for the treatment of HNSCC has met with limited success. Apart from the anti-EGFR antibody cetuximab, no small molecule EGFR/tyrosine kinase inhibitors (TKIs) have progressed to routine clinical use. The aim of this study was to determine factors contributing to the lack of response to TKIs and identify alternative therapeutic vulnerabilities. METHODS: Genomic and transcriptomic sequencing, high-throughput compound screens, overexpression and siRNA knockdown, western blot, in vivo xenograft studies. FINDINGS: We derived three pairs of isogenic gefitinib (TKI)-sensitive and resistant patient-derived HNSCC cell lines. Genomic sequencing of gefitinib-resistant cell lines identified a lack of activating and resistance-associated EGFR mutations. Instead, transcriptomic sequencing showed upregulated EMT gene signature in the gefitinib-resistant cells with a corresponding increase in their migratory phenotype. Additionally, the resistant cell displayed reduced growth rate. Surprisingly, while gefitinib-resistant cells were independent of EGFR for survival, they nonetheless displayed activation of downstream ERK and AKT signalling. High-throughput screening (HTS) of druggable, small molecule libraries revealed that the gefitinib-resistant cells were particularly sensitive to inhibitors of genes involved in cell cycle and mitosis, such as Aurora kinase inhibitors (AKIs), cyclin-dependent kinase (CDK) inhibitors, and microtubule inhibitors. Notably our results showed that in the EGFR inhibited state, Aurora kinases are essential for cell survival. INTERPRETATION: Our study demonstrates that in the absence of activating EGFR mutations, HNSCCs may gain resistance to gefitinib through decreased cell proliferation, which makes them exceptionally vulnerable to cell-cycle inhibitors. FUNDING: Agency for Science, Technology, and Research (A*STAR), National Medical Research Council (NMRC), and the National Institutes of Health (NIH)/National Cancer Institute (NCI).


Assuntos
Aurora Quinases/antagonistas & inibidores , Aurora Quinases/metabolismo , Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Gefitinibe/farmacologia , Mutação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/genética , Imunofluorescência , Humanos , Modelos Biológicos , Bibliotecas de Moléculas Pequenas , Carcinoma de Células Escamosas de Cabeça e Pescoço
5.
Commun Biol ; 3(1): 701, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219324

RESUMO

Mitosis has been validated by numerous anti-cancer drugs as being a druggable process, and selective inhibition of parasite proliferation provides an obvious opportunity for therapeutic intervention against malaria. Mitosis is controlled through the interplay between several protein kinases and phosphatases. We show here that inhibitors of human mitotic kinases belonging to the Aurora family inhibit P. falciparum proliferation in vitro with various potencies, and that a genetic selection for mutant parasites resistant to one of the drugs, Hesperadin, identifies a resistance mechanism mediated by a member of a different kinase family, PfNek1 (PF3D7_1228300). Intriguingly, loss of PfNek1 catalytic activity provides protection against drug action. This points to an undescribed functional interaction between Ark and Nek kinases and shows that existing inhibitors can be used to validate additional essential and druggable kinase functions in the parasite.


Assuntos
Aurora Quinases , Epistasia Genética , Indóis/farmacologia , Quinase 1 Relacionada a NIMA , Plasmodium falciparum , Sulfonamidas/farmacologia , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/química , Aurora Quinases/metabolismo , Epistasia Genética/efeitos dos fármacos , Epistasia Genética/genética , Humanos , Quinase 1 Relacionada a NIMA/química , Quinase 1 Relacionada a NIMA/genética , Quinase 1 Relacionada a NIMA/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo
6.
Mutat Res ; 821: 111716, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32738522

RESUMO

It is well established that Aurora kinases perform critical functions during mitosis. It has become increasingly clear that the Aurora kinases also perform a myriad of non-mitotic functions including DNA damage response. The available evidence indicates that inhibition Aurora kinase A (AURKA) may contribute to the G2 DNA damage checkpoint through AURKA's functions in PLK1 and CDC25B activation. Both AURKA and Aurora kinase B (AURKB) are also essential in mitotic DNA damage response that guard against DNA damage-induced chromosome segregation errors, including the control of abscission checkpoint and prevention of micronuclei formation. Dysregulation of Aurora kinases can trigger DNA damage in mitosis that is sensed in the subsequent G1 by a p53-dependent postmitotic checkpoint. Aurora kinases are themselves linked to the G1 DNA damage checkpoint through p53 and p73 pathways. Finally, several lines of evidence provide a connection between Aurora kinases and DNA repair and apoptotic pathways. Although more studies are required to provide a comprehensive picture of how cells respond to DNA damage, these findings indicate that both AURKA and AURKB are inextricably linked to pathways guarding against DNA damage. They also provide a rationale to support more detailed studies on the synergism between small-molecule inhibitors against Aurora kinases and DNA-damaging agents in cancer therapies.


Assuntos
Antineoplásicos/uso terapêutico , Aurora Quinases/antagonistas & inibidores , Dano ao DNA , Reparo do DNA , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Animais , Humanos , Neoplasias/genética , Neoplasias/patologia
7.
Eur J Med Chem ; 203: 112498, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32693295

RESUMO

Non-infectious and chronic diseases such as malignant tumors are now one of the main causes of human death. Its occurrence is a multi-factor, multi-step complex process with biological characteristics such as cell differentiation, abnormal proliferation, uncontrolled growth, and metastasis. It has been found that a variety of human malignant tumors are accompanied by over-expression and proliferation of Aurora kinase, which causes abnormalities in the mitotic process and is related to the instability of the genome that causes tumors. Therefore, the use of Aurora kinase inhibitors to target tumors is becoming a research hotspot. However, in cancer, because of the complexity of signal transduction system and the participation of different proteins and enzymes, the anticancer effect of selective single-target drugs is limited. After inhibiting one pathway, signal molecules can be conducted through other pathways, resulting in poor therapeutic effect of single-target drug treatment. Multi-target drugs can solve this problem very well. It can regulate the various links that cause disease at the same time without completely eliminating the relationship between the signal transmission systems, and it is not easy to cause drug resistance. Currently, studies have shown that Aurora dual-target inhibitors generated with the co-inhibition of Aurora and another target (such as CDK, PLK, JAK2, etc.) have better therapeutic effects on tumors. In this paper, we reviewed the studies of dual Aurora inhibitors that have been discovered in recent years.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Humanos , Inibidores de Proteínas Quinases/química
8.
Clin Epigenetics ; 12(1): 93, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586373

RESUMO

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined. RESULTS: We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3' exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3'UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5' UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors. CONCLUSIONS: Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.


Assuntos
Linhagem Celular Tumoral/efeitos dos fármacos , Metilação de DNA/genética , Epigenoma/genética , Carcinoma de Pequenas Células do Pulmão/genética , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Inibidoras de Quinase Dependente de Ciclina/farmacologia , Metilação de DNA/efeitos dos fármacos , Quimioterapia Combinada/estatística & dados numéricos , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histona Desmetilases/efeitos dos fármacos , Histona Desmetilases/genética , Humanos , Neoplasias Pulmonares/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/diagnóstico
9.
Mini Rev Med Chem ; 20(14): 1375-1388, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348219

RESUMO

The scientists, and the researchers around the globe generate tremendous amount of information everyday; for instance, so far more than 74 million molecules are registered in Chemical Abstract Services. According to a recent study, at present we have around 1060 molecules, which are classified as new drug-like molecules. The library of such molecules is now considered as 'dark chemical space' or 'dark chemistry.' Now, in order to explore such hidden molecules scientifically, a good number of live and updated databases (protein, cell, tissues, structure, drugs, etc.) are available today. The synchronization of the three different sciences: 'genomics', proteomics and 'in-silico simulation' will revolutionize the process of drug discovery. The screening of a sizable number of drugs like molecules is a challenge and it must be treated in an efficient manner. Virtual screening (VS) is an important computational tool in the drug discovery process; however, experimental verification of the drugs also equally important for the drug development process. The quantitative structure-activity relationship (QSAR) analysis is one of the machine learning technique, which is extensively used in VS techniques. QSAR is well-known for its high and fast throughput screening with a satisfactory hit rate. The QSAR model building involves (i) chemo-genomics data collection from a database or literature (ii) Calculation of right descriptors from molecular representation (iii) establishing a relationship (model) between biological activity and the selected descriptors (iv) application of QSAR model to predict the biological property for the molecules. All the hits obtained by the VS technique needs to be experimentally verified. The present mini-review highlights: the web-based machine learning tools, the role of QSAR in VS techniques, successful applications of QSAR based VS leading to the drug discovery and advantages and challenges of QSAR.


Assuntos
Desenho de Fármacos , Relação Quantitativa Estrutura-Atividade , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/metabolismo , Ligantes , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Bioorg Chem ; 98: 103689, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171993

RESUMO

In an effort to develop new cancer therapeutics, we have reported clinical candidate BPR1K871 (1) as a potentanticancercompound in MOLM-13 and MV4-11 leukemia models, as well as in colorectal and pancreatic animal models. As BPR1K871 lacks oral bioavailability, we continued searching for orally bioavailable analogs through drug-like property optimization. We optimized both the physicochemical properties (PCP) as well as in vitro rat liver microsomal stability of 1, with concomitant monitoring of aurora kinase enzyme inhibition as well as cellular anti-proliferative activity in HCT-116 cell line. Structural modification at the 6- and 7-position of quinazoline core of 1 led to the identification of 34 as an orally bioavailable (F% = 54) multi-kinase inhibitor, which exhibits potent anti-proliferative activity against various cancer cell lines. Quinazoline 34 is selected as a promising oral lead candidate for further preclinical evaluation.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Aurora Quinases/metabolismo , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Masculino , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Quinazolinas/administração & dosagem , Quinazolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
11.
J Mol Med (Berl) ; 98(4): 495-512, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32219470

RESUMO

Glioblastoma is the most common aggressive primary brain tumor. Standard care includes maximal safe surgical resection, radiation, and chemotherapy with temozolomide. However, the impact of this therapeutic approach on patient survival is disappointing and poor outcomes are frequently observed. Therefore, new therapeutic targets are needed to treat this potentially deadly tumor. Aurora kinases are one of today's most sought-after classes of therapeutic targets to glioblastoma therapy. They are a family of proteins composed of three members: Aurora-A, Aurora-B, and Aurora-C that play different roles in the cell division through regulation of chromosome segregation. Deregulation of these genes has been reported in glioblastoma and a progressive number of studies have shown that inhibition of these proteins could be a promising strategy for the treatment of this tumor. This review discusses the preclinical and early clinical findings on the potential use of the Aurora kinases as new targets for the treatment of glioblastoma. KEY MESSAGES: GBM is a very aggressive tumor with limited therapeutic options. Aurora kinases are a family of serine/threonine kinases implicated in GBM pathology. Aurora kinases are critical for glioblastoma cell growth, apoptosis, and chemoresistance. Inhibition of Aurora kinases has a synergistic or sensitizing effect with chemotherapy drugs, radiotherapy, or with other targeted molecules in GBM. Several Aurora kinase inhibitors are currently in clinical trials.


Assuntos
Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Glioblastoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Aurora Quinases/genética , Aurora Quinases/metabolismo , Biomarcadores Tumorais , Glioblastoma/tratamento farmacológico , Glioblastoma/etiologia , Glioblastoma/patologia , Humanos , Terapia de Alvo Molecular , Família Multigênica , Inibidores de Proteínas Quinases/uso terapêutico , Pesquisa Médica Translacional , Ensaios Antitumorais Modelo de Xenoenxerto
12.
ACS Chem Biol ; 15(3): 669-674, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32004428

RESUMO

While recognized as a therapeutic target, the spliceosome may offer a robust vector to improve established therapeutics against other protein targets. Here, we describe how modulating the spliceosome using small molecule splice modulators (SPLMs) can prime a cell for sensitivity to a target-specific drug. Using the cell cycle regulators aurora kinase and polo-like kinase as models, this study demonstrates how the combination of SPLM treatment in conjunction with kinase inhibition offers synergy for antitumor activity using reduced, sublethal levels of SPLM and kinase inhibitors. This concept of splice-modulated drug attenuation suggests a possible approach to enhance therapeutic agents that have shown limited applicability due to high toxicity or low efficacy.


Assuntos
Antineoplásicos/química , Aurora Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Antineoplásicos/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Macrolídeos/química , Macrolídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/química , Pteridinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Especificidade por Substrato
13.
J Pathol ; 250(2): 159-169, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31595974

RESUMO

Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Família Aldeído Desidrogenase 1/metabolismo , Antineoplásicos/farmacologia , Cistadenocarcinoma Seroso/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/patologia , Retinal Desidrogenase/metabolismo , Aurora Quinases/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante/métodos , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Gradação de Tumores , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Prognóstico , Esferoides Celulares/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Células Tumorais Cultivadas/efeitos dos fármacos
14.
J Proteome Res ; 18(11): 3850-3866, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560547

RESUMO

Neuroblastoma is a neural crest-derived embryonal tumor and accounts for about 15% of all cancer deaths in children. MYCN amplification is associated with aggressive and advanced stage of high-risk neuroblastoma, which remains difficult to treat and exhibits poor survival under current multimodality treatment. Here, we analyzed the transcriptomic profiles of neuroblastoma patients and showed that aurora kinases lead to poor survival and had positive correlation with MYCN amplification and high-risk disease. Further, pan-aurora kinase inhibitor (tozasertib) treatment not only induces cell-cycle arrest and suppresses cell proliferation, migration, and invasion ability in MYCN-amplified (MNA) neuroblastoma cell lines, but also inhibits tumor growth and prolongs animal survival in Th-MYCN transgenic mice. Moreover, we performed quantitative proteomics and identified 150 differentially expressed proteins after tozasertib treatment in the Th-MYCN mouse model. The functional and network-based enrichment revealed that tozasertib alters metabolic processes and identified a mitochondrial flavoenzyme in fatty acid ß-oxidation, ACADM, which is correlated with aurora kinases and neuroblastoma patient survival. Our findings indicate that the aurora kinase inhibitor could cause metabolic imbalance, possibly by disturbing carbohydrate and fatty acid metabolic pathways, and ACADM may be a potential target in MNA neuroblastoma.


Assuntos
Acil-CoA Desidrogenase/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteômica/métodos , Acil-CoA Desidrogenase/genética , Animais , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/genética , Aurora Quinases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/genética , Camundongos da Linhagem 129 , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Piperazinas/farmacologia , Análise de Sobrevida
15.
OMICS ; 23(10): 486-495, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31549911

RESUMO

Thyroid cancer (TC) is a very common malignancy worldwide. Chief among the innovative molecular drug targets for TC are epigenetic modifications. Increased telomerase activity in cancer cells makes telomerase a novel target for epigenetic anticancer drug innovation. Recently, telomerase reverse transcriptase (TERT) gene promoter (TERTp) mutations (C228T and C250T) were reported at high frequency in TC cell lines and tumor biopsies. In this study, three representative TC cell lines, mutant TERTp (TPC1), mutant BRAF/TERTp (KTC2), and wild-type TERTp (WRO), were screened with a drug library composed of 51 epigenetic drugs: 14 Aurora kinase inhibitors; 23 histone deacetylase inhibitors; 5 sirtuin modifiers; 3 hypoxia-inducible factor inhibitors; 2 DNA methyltransferase inhibitors; 2 histone methyltransferase inhibitors, a histone demethylase inhibitor, and a bromodomain inhibitor. Effects of the drugs on cell growth at 48 and 72 h were compared. PF-03814735, a small-molecule inhibitor of Aurora kinase A (IC50 = 0.8 nM) and B (IC50 = 5 nM), was the most potent on KTC2 cells, whereas CUDC-101, a multitarget inhibitor, was effective on both WRO and KTC2 cells. Notably, PF-03814735 was found to be the most effective epigenetic drug on cell lines harboring the C228T mutation. In conclusion, these new findings offer specific guidance on dose and time course selection to design novel therapeutic interventions against TC using PF-03814735, and specifically target cells carrying the TERTpC228T mutation. In a larger context of drug discovery science, these findings inform new strategies to forecast optimal treatment regimens for TC, particularly with Aurora kinase inhibitors and in ways guided by epigenetic drug design.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/química , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Biomarcadores Tumorais , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Humanos , Mutação , Telomerase/genética , Neoplasias da Glândula Tireoide
16.
Sci Rep ; 9(1): 9943, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289333

RESUMO

Melanoma is the most serious form of skin cancer but its medication is still far from being safe and thoroughly effective. The search of novel therapeutic approaches represents therefore a health emergency to push through eagerly. In this study, we describe a novel class of dual c-Kit/Aur inhibitors, characterized by a 1,2,4-triazole core and developed by a structure-based optimization of a previously developed hit, and report the evidence of their significance as drug candidates for the treatment of melanoma. Compound 6a, merging the best inhibitory profile against the target kinases, showed anti-proliferative efficacy against the human melanoma cell lines A2058, expressing the BRAF V600D mutation, and WM266-4, expressing BRAF V600E. Significantly, it displayed also a highly synergistic profile when tested in combination with vemurafenib, thus proving its efficacy not only per se but even in a combination therapy, which is nowadays acknowledged as the cornerstone approach of the forthcoming tumour management.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Desenho de Fármacos , Melanoma/tratamento farmacológico , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proliferação de Células , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Células Tumorais Cultivadas
17.
Mol Biol Cell ; 30(14): 1691-1704, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31067151

RESUMO

Oocytes of many species lack centrioles and therefore form acentriolar spindles. Despite the necessity of oocyte meiosis for successful reproduction, how these spindles mediate accurate chromosome segregation is poorly understood. We have gained insight into this process through studies of the kinesin-4 family member Kif4 in mouse oocytes. We found that Kif4 localizes to chromosomes through metaphase and then largely redistributes to the spindle midzone during anaphase, transitioning from stretches along microtubules to distinct ring-like structures; these structures then appear to fuse together by telophase. Kif4's binding partner PRC1 and MgcRacGAP, a component of the centralspindlin complex, have a similar localization pattern, demonstrating dynamic spindle midzone organization in oocytes. Kif4 knockdown results in defective midzone formation and longer spindles, revealing new anaphase roles for Kif4 in mouse oocytes. Moreover, inhibition of Aurora B/C kinases results in Kif4 mislocalization and causes anaphase defects. Taken together, our work reveals essential roles for Kif4 during the meiotic divisions, furthering our understanding of mechanisms promoting accurate chromosome segregation in acentriolar oocytes.


Assuntos
Anáfase , Proteínas de Ligação a DNA/metabolismo , Cinesina/metabolismo , Meiose , Proteínas Nucleares/metabolismo , Oócitos/citologia , Oócitos/metabolismo , Animais , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/metabolismo , Camundongos , Modelos Biológicos , Fuso Acromático/metabolismo
18.
PLoS Negl Trop Dis ; 13(5): e0007425, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095613

RESUMO

BACKGROUND: The tumor-like growth of the metacestode larvae of the tapeworm E. multilocularis causes human alveolar echinococcosis, a severe disease mainly affecting the liver. The germinative cells, a population of adult stem cells, are crucial for the larval growth and development of the parasite within the hosts. Maintenance of the germinative cell pools relies on their abilities of extensive proliferation and self-renewal, which requires accurate control of the cell division cycle. Targeting regulators of the cell division progression may impair germinative cell populations, leading to impeded parasite growth. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we describe the characterization of EmAURKA and EmAURKB, which display significant similarity to the members of Aurora kinases that are essential mitotic kinases and play key roles in cell division. Our data suggest that EmAURKA and EmAURKB are actively expressed in the germinative cells of E. multilocularis. Treatment with low concentrations of MLN8237, a dual inhibitor of Aurora A and B, resulted in chromosomal defects in the germinative cells during mitosis, while higher concentrations of MLN8237 caused a failure in cytokinesis of the germinative cells, leading to multinucleated cells. Inhibition of the activities of Aurora kinases eventually resulted in depletion of the germinative cell populations in E. multilocularis, which in turn caused larval growth inhibition of the parasite. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the vital roles of Aurora kinases in the regulation of mitotic progression and maintenance of the germinative cells in E. multilocularis, and suggest Aurora kinases as promising druggable targets for the development of novel chemotherapeutics against human alveolar echinococcosis.


Assuntos
Aurora Quinases/metabolismo , Equinococose/parasitologia , Echinococcus multilocularis/enzimologia , Echinococcus multilocularis/crescimento & desenvolvimento , Proteínas de Helminto/metabolismo , Sequência de Aminoácidos , Animais , Aurora Quinases/antagonistas & inibidores , Aurora Quinases/química , Aurora Quinases/genética , Azepinas/farmacologia , Clonagem Molecular , Echinococcus multilocularis/efeitos dos fármacos , Echinococcus multilocularis/genética , Proteínas de Helminto/antagonistas & inibidores , Proteínas de Helminto/química , Proteínas de Helminto/genética , Humanos , Larva/enzimologia , Larva/genética , Larva/crescimento & desenvolvimento , Mitose , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Alinhamento de Sequência
19.
Eur J Pharm Sci ; 139: 104899, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30953752

RESUMO

CCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CLint) determination and metabolite profiling of CCT241736 in human and four preclinical species (dog, minipig, rat and mouse) was undertaken in cryopreserved hepatocytes and liver microsomes. Recombinant human cytochrome P450 bactosomes (rCYP) were utilised to provide reaction phenotyping data and support prediction of metabolic pathways. CCT241736 exhibited low CLint in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CLint in mouse. CYP3A4 and CYP3A5 were identified as the major enzymes responsible for biotransformation of CCT241736 in human, exclusively forming five out of seven metabolites. Minipig showed greatest similarity to human with regard to both overall metabolic profile and abundance of specific metabolites relative to parent compound, and is therefore proposed as the most appropriate toxicological species. The greatest disparity was observed between human and dog. Based on metabolic profile, either mouse or rat is a suitable rodent species for toxicology studies.


Assuntos
Aurora Quinases/antagonistas & inibidores , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura , Testes de Toxicidade
20.
Mol Med Rep ; 19(5): 3841-3847, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816538

RESUMO

Angiogenesis serves a key role in tumor growth and metastasis. VX­680, a potent inhibitor targeting the Aurora kinase family, is widely used in the inhibition of tumor progression. However, the effect of VX­680 on angiogenesis remains unknown. The present study identified that VX­680 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and promoted HUVEC apoptosis by inducing the cleavage of PARP and caspase­3. VX­680 also markedly decreased the migration and tube formation of HUVECs in a dose­dependent manner. In addition, VX­680 significantly suppressed the formation of blood vessels in a dose­dependent manner confirmed by a chicken embryo chorioallantoic membrane assay in vivo. Furthermore, VX­680 inhibited the expression levels of vascular endothelial growth factor and phosphorylated RAC­α serine/threonine­protein kinase in HUVECs. These results suggested that VX­680 suppressed angiogenesis and may be a potential novel anti­angiogenic agent.


Assuntos
Aurora Quinases/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Membrana Corioalantoide/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Piperazinas/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Humanos
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