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2.
Mol Cancer Ther ; 15(4): 628-39, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26939704

RESUMO

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. Mol Cancer Ther; 15(4); 628-39. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinase do Linfoma Anaplásico , Animais , Benzamidas/química , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Humanos , Indazóis/química , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Mortalidade , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Translocação Genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Med Chem ; 59(7): 3392-408, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-27003761

RESUMO

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Descoberta de Drogas , Indazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzamidas/administração & dosagem , Benzamidas/química , Barreira Hematoencefálica/efeitos dos fármacos , Western Blotting , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cristalização , Cristalografia por Raios X , Cães , Humanos , Indazóis/administração & dosagem , Indazóis/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Camundongos SCID , Microssomos Hepáticos/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Ratos , Ratos Wistar , Receptor trkA/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Receptor trkC/antagonistas & inibidores , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Natl Cancer Inst ; 108(1)2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26563355

RESUMO

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fusão Gênica , Rearranjo Gênico , Lamina Tipo A/genética , Neoplasias Hepáticas/tratamento farmacológico , Proteínas/genética , Receptor trkA/genética , Idoso , Quinase do Linfoma Anaplásico , Antineoplásicos/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Lamina Tipo A/antagonistas & inibidores , Neoplasias Hepáticas/secundário , Terapia de Alvo Molecular , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor trkA/antagonistas & inibidores
5.
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
6.
Mol Oncol ; 8(8): 1495-507, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24962792

RESUMO

The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. We report the detailed characterization of the TPM3-NTRK1 genomic rearrangement in KM12 cells and through a cellular screening approach, the identification of NMS-P626, a novel highly potent and selective TRKA inhibitor. NMS-P626 suppressed TPM3-TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors. Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Tropomiosina/metabolismo , Animais , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Imunoprecipitação , Técnicas In Vitro , Camundongos , Ligação Proteica/efeitos dos fármacos
7.
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
8.
9.
Bioorg Med Chem Lett ; 20(14): 4095-9, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20621725

RESUMO

In this Letter is described the structure-based design of potent dihydro-pyrazoloquinazolines as PDK1 inhibitors. Starting from low potency HTS hits with the aid of X-ray crystallography and modeling, a medicinal chemistry activity was carried out to improve potency versus PDK1 and selectivity versus CDK2 protein kinase.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia
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