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1.
ChemMedChem ; 10(2): 276-95, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25430902

RESUMO

Aberrant activation of the mitogen-activated protein kinase (MAPK)-mediated pathway components, RAF-MEK-ERK, is frequently observed in human cancers and clearly contributes to oncogenesis. As part of a project aimed at finding inhibitors of B-Raf, a key player in the MAPK cascade, we originally identified a thiazole derivative endowed with high potency and selectivity, optimal in vitro ADME properties, and good pharmacokinetic profiles in rodents, but that suffers from elevated hERG inhibitory activity. An optimization program was thus undertaken, focused mainly on the elaboration of the R(1) and R(2) groups of the scaffold. This effort ultimately led to N-(4-{2-(1-cyclopropylpiperidin-4-yl)-4-[3-(2,5-difluorobenzenesulfonylamino)-2-fluorophenyl]thiazol-5-yl}-pyridin-2-yl)acetamide (20), which maintains favorable in vitro and in vivo properties, but lacks hERG liability. Besides exhibiting potent antiproliferative activity against only cell lines bearing B-Raf V600E or V600D mutations, compound 20 also intriguingly shows a weaker "paradoxical" activation of MEK in non-mutant B-Raf cells than other known B-Raf inhibitors. It also demonstrates very good efficacy in vivo against the A375 xenograft melanoma model (tumor volume inhibition >90% at 10 mg kg(-1) ); it is therefore a suitable candidate for preclinical development.


Assuntos
Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/química , Tiazóis/química , Administração Oral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Sulfonamidas/uso terapêutico , Sulfonamidas/toxicidade , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Tiazóis/toxicidade , Transplante Heterólogo
2.
Exp Cell Res ; 332(2): 267-77, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25486070

RESUMO

Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.


Assuntos
Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética
3.
Drug Discov Today Technol ; 11: 5-10, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24847647

RESUMO

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with Imatinib in patients with chronic myelogenous leukaemia (CML). Second generation Bcr-Abl inhibitors, such as Nilotinib and Dasatinib, are able to overcome most Imatinib- resistant mutants, with the exception of the T315I substitution. Structural studies of Abl wild-type and T315I mutant have provided better understanding of how this mutation leads to resistance and have been used to support the drug design process for the development of inhibitors able to target the T315I substitution.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Descoberta de Drogas , Humanos , Proteínas Proto-Oncogênicas c-abl/genética
4.
Sci Rep ; 3: 3128, 2013 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-24185259

RESUMO

We show that a category of one-dimensional XY-type models may enable high-fidelity quantum state transmissions, regardless of details of coupling configurations. This observation leads to a fault-tolerant design of a state transmission setup. The setup is fault-tolerant, with specified thresholds, against engineering failures of coupling configurations, fabrication imperfections or defects, and even time-dependent noises. We propose an experimental implementation of the fault-tolerant scheme using hard-core bosons in one-dimensional optical lattices.

5.
6.
Bioorg Med Chem Lett ; 22(12): 3951-6, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22608393

RESUMO

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.


Assuntos
Antineoplásicos/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Sulfonamidas/síntese química , Proteína X Associada a bcl-2/antagonistas & inibidores , Proteína bcl-X/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Citocromos c/metabolismo , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Ligação Proteica , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/química , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/química , Proteína bcl-X/metabolismo
7.
J Biol Chem ; 285(16): 11775-85, 2010 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-20177074

RESUMO

Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.


Assuntos
Proteínas Nucleares/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Aurora Quinase B , Aurora Quinases , Sítios de Ligação , Linhagem Celular , Células HeLa , Humanos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas de Transporte Nucleocitoplasmático/antagonistas & inibidores , Proteínas de Transporte Nucleocitoplasmático/química , Proteínas de Transporte Nucleocitoplasmático/genética , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina/química , Especificidade por Substrato
8.
Nature ; 453(7197): 895-8, 2008 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-18548066

RESUMO

Anderson localization of waves in disordered media was originally predicted fifty years ago, in the context of transport of electrons in crystals. The phenomenon is much more general and has been observed in a variety of systems, including light waves. However, Anderson localization has not been observed directly for matter waves. Owing to the high degree of control over most of the system parameters (in particular the interaction strength), ultracold atoms offer opportunities for the study of disorder-induced localization. Here we use a non-interacting Bose-Einstein condensate to study Anderson localization. The experiment is performed with a one-dimensional quasi-periodic lattice-a system that features a crossover between extended and exponentially localized states, as in the case of purely random disorder in higher dimensions. Localization is clearly demonstrated through investigations of the transport properties and spatial and momentum distributions. We characterize the crossover, finding that the critical disorder strength scales with the tunnelling energy of the atoms in the lattice. This controllable system may be used to investigate the interplay of disorder and interaction (ref. 7 and references therein), and to explore exotic quantum phases.

9.
Cancer Res ; 67(17): 7987-90, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17804707

RESUMO

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with imatinib in patients with chronic myelogenous leukemia (CML). Second-generation Bcr-Abl inhibitors are able to overcome most imatinib-resistant mutants, with the exception of the frequent T315I substitution, which is emerging as a major cause of resistance to these drugs in CML patients. Structural studies could be used to support the drug design process for the development of inhibitors able to target the T315I substitution, but until now no crystal structure of the T315I Abl mutant has been solved. We show here the first crystal structure of the kinase domain of Abl T315I in complex with PHA-739358, an Aurora kinase inhibitor currently in clinical development for solid and hematologic malignancies. This compound inhibits in vitro the kinase activity of wild-type Abl and of several mutants, including T315I. The cocrystal structure of T315I Abl kinase domain provides the structural basis for this activity: the inhibitor associates with an active conformation of the kinase domain in the ATP-binding pocket and lacks the steric hindrance imposed by the substitution of threonine by isoleucine.


Assuntos
Benzamidas/química , Benzamidas/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-abl/genética , Pirazóis/química , Pirazóis/metabolismo , Aurora Quinases , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Mesilato de Imatinib , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Piperazinas/farmacologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirimidinas/farmacologia
10.
J Med Chem ; 49(11): 3278-86, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16722646

RESUMO

A computational protocol was applied to identify molecular scaffolds untested toward the c-Src tyrosine kinase. A combination of docking and dynamics calculations allowed us to build three-dimensional models of the complexes between Src and several of its known inhibitors. Interactions most contributing to activity of the inhibitors, in terms of hydrogen bonds and hydrophobic contacts, were codified into pharmacophoric models that were in turn applied to perform a search of commercially available compounds within the Asinex database. As a result, we identified 1,3,4-thiadiazoles and pyrazolydine-3,5-diones showing inhibitory activity in the submicromolar range in a cell-free assay toward Src. Moreover, since several of the compounds used to generate pharmacophores were also known as Abl inhibitors, we tested the identified hits toward Abl tyrosine kinase, finding activity in the submicromolar range. Such biological data suggested that the computational protocol is an efficient tool for identifying new hits toward both Src and Abl.


Assuntos
Modelos Moleculares , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/química , Humanos , Pirazóis/química , Relação Estrutura-Atividade , Tiadiazóis/química , Quinases da Família src
11.
J Med Chem ; 49(5): 1549-61, 2006 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-16509573

RESUMO

We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.


Assuntos
Antineoplásicos/síntese química , Apoptose , Pirazóis/síntese química , Pirimidinas/síntese química , Quinases da Família src/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ciclinas/antagonistas & inibidores , Ciclinas/biossíntese , Ciclinas/genética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , RNA Mensageiro/biossíntese
12.
Oncogene ; 21(49): 7478-87, 2002 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-12386810

RESUMO

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression.


Assuntos
Regulação para Baixo/fisiologia , Metástase Neoplásica , Receptores de Laminina/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Sequência de Bases , Western Blotting , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/fisiopatologia , Testes de Precipitina , Células Tumorais Cultivadas
13.
Cancer Res ; 62(5): 1321-5, 2002 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11888899

RESUMO

The 67-kDa laminin receptor (67LR) is a high-affinity laminin-binding protein that is overexpressed on the tumor cell surface in a variety of cancers. We report here that the 67LR molecule also functions in the proteolytic cleavage of laminin-1, a relevant event in basement membrane degradation and tumor dissemination. In the presence of a synthetic peptide (peptide G) corresponding to the 67LR laminin binding site, the rate of laminin-1 degradation by the cysteine proteinase cathepsin B was significantly increased, and a new proteolytic fragment particularly active in in vitro cell migration assays was generated. The YIGSR peptide, corresponding to the 67LR binding site on laminin-1, blocked the peptide G-dependent proteolytic degradation. Our results shed light on the mechanism by which an adhesion receptor such as the 67LR plays a major role in tumor aggressiveness and metastasis.


Assuntos
Laminina/metabolismo , Neoplasias/patologia , Receptores de Laminina/fisiologia , Sequência de Aminoácidos , Animais , Adesão Celular , Divisão Celular , Movimento Celular , Feminino , Humanos , Camundongos , Dados de Sequência Molecular , Peso Molecular , Células Tumorais Cultivadas
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