PT1590340E - Inibidores de histona desacetilase - Google Patents
Inibidores de histona desacetilase Download PDFInfo
- Publication number
- PT1590340E PT1590340E PT04707852T PT04707852T PT1590340E PT 1590340 E PT1590340 E PT 1590340E PT 04707852 T PT04707852 T PT 04707852T PT 04707852 T PT04707852 T PT 04707852T PT 1590340 E PT1590340 E PT 1590340E
- Authority
- PT
- Portugal
- Prior art keywords
- compound
- histone deacetylase
- hdac
- inhibition
- human
- Prior art date
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Description
1
DESCRIÇÃO "INIBIDORES DE HISTONA DESACETILASE"
Esta invenção diz respeito à inibição da histona desacetilase. Mais especificamente, a invenção diz respeito a compostos úteis para inibir a actividade enzimática da histona desacetilase.
Resumo da Técnica Relacionada
Nas células eucariotas, o AND do núcleo associa-se com as histonas para formar um complexo compacto denominado cromatina. As histonas constituem uma familia de proteínas básicas que em geral são altamente mantidas através das espécies eucariotas. As histonas do núcleo, denominadas H2A, H2B, H3, e H4, associam-se para formarem um núcleo proteico. 0 AND enrola-se em torno deste núcleo proteico, com interacções entre os aminoácidos básicos das histonas e os grupos fosfato com carga negativa do ADN. Cerca de 146 pares de bases do ADN enrolam-se em torno de um núcleo de histona para constituírem uma partícula de nucleossoma, unidade estrutural repetitiva da cromatina.
Csordas, Biochem. J., 286: 23-38 (1990) ensina que as histonas estão submetidas à acetilação pós- 2 translacional dos grupos αΕε-amino dos resíduos de lisina do terminal N, uma reacção que é catalisada pela histona acetil transferase (HAT1). A acetilação neutraliza a carga positiva da cadeia lateral com lisina, e crê-se que tenha impacto sobre a estrutura da cromatina. De facto, Taunton et ai., Science, 272: 408-411 (1996), ensinam que o acesso dos factores de transcrição às estruturas de cromatina é melhorado por hiperacetilação da histona. Taunton et ai. ensinam também que se encontrou um enriquecimento na histona H4 subacetilada que é encontrada nas regiões transcricionalmente silenciosas do genoma. A acetilação da histona é uma modificação reversível, e a desacetilação é catalisada por uma família de enzimas denominados histona desacetilases (HDAC). Grozinger et al., Proc. Natl. Acad. Sei. USA, 96: 4868-4873 (1999), ensinam que as HDAC se dividem em duas classes, a primeira representada por proteínas semelhantes a Rpd3 das leveduras, e a segunda representada pelas proteínas semelhantes a Hdal das leveduras. Grozinger et ai. também ensinam que as proteínas HDACl, HDAC2, e HDAC3 humanas são membros da primeira classe de HDAC, e descrevem novas proteínas, denominadas HDAC4 , HDAC5, e HDAC6, que são membros da segunda classe de HDAC. Kao et ai., Genes &
Dev., 14: 55-66 (2000), descrevem HDAC7, um novo membro da segunda classe de HDAC. Van den Wyngaert, FEBS, 478: 77-83 3 (2000) descreve a HDAC8, um novo membro da primeira classe de HDAC.
Richon et al., Proc. Natl. Acad. Sei. USA, 95: 3003-3007 (1998), descrevem que a actividade de HDAC é inibida pela tricoestatina A (TSA), um produto natural isolado de Streptomyces hygroscopicus, e por um composto sintético, o ácido suberoilanilida-hidroxâmico (SAHA). Yoshida e Beppu, Exper. Cell Res., 177: 122-131 (1988), ensinam que TSA provoca a paragem dos fibroblastos do rato nas fases Gi e G2 do ciclo celular, implicando as HDAC na regulação do ciclo celular. De facto, Finnin et al., Nature, 401: 188-193 (1999), ensinam que TSA e SAHA inibem o crescimento celular, induzem a diferenciação terminal, e impedem a formação de tumores em murganhos. Suzuki et al., na Patente U.S. No. 6.174.905, na EP 0 847.992, na JP 258.863/96, e no pedido Japonês No. 10.138.957, descrevem derivados de benzamida que induzem a diferenciação celular e que inibem as HDAC. Delorme et al., WO 01/38.322 e PCT IB 01/00.683, descrevem compostos adicionais que servem como inibidores de HDAC. A clonagem molecular de sequências genéticas codificando para proteinas com actividade de HDAC estabeleceu a existência de um conjunto de isoformas diversas de enzimas HDAC. Grozinger et al., Proc. Natl. Acad. Sei. USA, 96: 4868-4873 (1999) ensinam que se podem classificar as HDAC em duas classes, sendo a primeira representada por proteinas semelhantes às Rpd3 de levedura, 4 e as segundas representada por proteínas semelhantes às Hdal de leveduras. Grozinger et al. também ensinam que as proteínas HDAC-1, HDAC-2, e HDAC-3 humanas são membros da primeira classe de HDAC, e descrevem novas proteínas, denominadas HDAC-4, HDAC-5, e HDAC-6, que são membros da segunda classe de HDAC. Kao et al., Gene & Development 14: 55-66 (2000), descrevem um membro adicional desta segunda classe, denominado HDAC-7. Mais recentemente, Hu, E. et al. J. Bio. Chem. 275: 15254-13264 (2000) descrevem o membro mais novo da primeira classe de histona desacetilases, HDAC-8. Permanece pouco claro quais os papéis desempenhados por estes enzimas HDAC individuais.
Estas descobertas sugerem que a inibição da actividade de HDAC representa um novo caminho para se intervir na regulação do ciclo celular, e que os inibidores de HDAC possuem um grande potencial terapêutico no tratamento de doenças ou de estados que incluam proliferação de células. Até à data, são conhecidos na técnica poucos inibidores de histona desacetilase. Existe portanto uma necessidade de se identificarem mais inibidores de HDAC, e de se identificarem as características estruturais necessárias para que exista uma actividade inibidora potente de HDAC.
BREVE RESUMO DA INVENÇÃO A invenção proporciona compostos úteis para tratar doenças das células que incluam a sua proliferação. 5 A invenção proporciona novos inibidores da actividade enzimática da histona desacetilase.
Num primeiro aspecto, a invenção proporciona compostos que são úteis a titulo de inibidores de histona desacetilase.
Num segundo aspecto, a invenção proporciona uma composição incluindo um inibidor de histona desacetilase de acordo com a invenção e um veiculo, excipiente ou diluente aceitável do ponto de vista farmacêutico.
Num terceiro aspecto, a invenção proporciona a utilização de um tal composto para a preparação de um medicamento para inibir a histona desacetilase numa célula.
Quanto precede apenas resume determinados aspectos da invenção, e não se pretende que tenha natureza limitativa. Estes aspectos e outros aspectos e concretizações estão descritos adiante em mais pormenor.
BREVE DESCRIÇÃO DOS DESENHOS A Figura 1 é um gráfico ilustrando a actividade antitumoral do composto 106 num modelo de tumor colo-rectal humano HCT 116. 6
As Figuras 2-11 mostram dados adicionais referentes a outros compostos utilizados na experiência in vivo que se descreve no Exemplo de Avaliação 2.
DESCRIÇÃO PORMENORIZADA DAS CONCRETIZAÇÕES
PREFERIDAS A invenção proporciona compostos e métodos para inibir a actividade enzimática da histona desacetilase. A invenção também proporciona composições e medicamentos para tratar doenças e estados que incluam proliferação de células. A literatura de patentes e cientifica a que se faz referência neste documento estabelece os conhecimentos que se encontram disponíveis para os indivíduos com conhecimentos da técnica.
Para os propósitos da invenção presente, utilizar-se-ão as definições que se seguem (a não ser onde se afirmar expressamente algo em contrário):
Tal como se utilizam neste documento, pretende-se que os termos "histona desacetilase" e "HDAC" refiram qualquer elemento de uma família de enzimas que removem grupos acetilo dos grupos amino α6ε dos resíduos de lisina no terminal N de uma histona. A não ser aonde seja contextualmente indicado algo em contrário, pretende-se que o termo "histona" se refira a qualquer proteína histona, 7 incluindo Hl, H2A, H2B, H3, H4, e H5, de qualquer espécie. Incluem-se nas histona desacetilases preferidas os enzimas da classe I e da classe II. Preferivelmente a histona desacetilase será uma HDAC humana, incluindo, mas não se limitando a, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, e HDAC-8. Em algumas das outras concretizações preferidas, a histona desacetilase é derivada de uma fonte tal como um protozoário ou um fungo. A expressão "inibidor de histona desacetilase" é utilizada para identificar um composto com uma estrutura tal como se define neste documento, que é capaz de interactuar com uma histona desacetilase e de inibir a sua actividade enzimática. "Inibir a actividade enzimática da histona desacetilase" significa diminuir a capacidade da histona desacetilase para remover um grupo acetilo de uma histona. Em algumas concretizações preferidas, esta diminuição da actividade da histona desacetilase é de pelo menos cerca de 50 %, mais preferivelmente em pelo menos cerca de 75 %, e ainda mais preferivelmente em pelo menos cerca de 90 %. Noutras concretizações preferidas, a actividade da histona desacetilase é diminuída em pelo menos 95 % e mais preferivelmente em pelo menos 99 %.
Preferivelmente, esta inibição é especifica, isto é, o inibidor de histona desacetilase diminui a capacidade de uma histona desacetilase para remover um grupo acetilo de uma histona, a uma concentração que seja inferior à concentração do inibidor que é necessária para originar outro efeito biológico não relacionado com este. Preferivelmente, a concentração do inibidor que é necessária para a actividade inibidora da histona desacetilase é pelo menos 2 vezes menor, mais preferivelmente pelo menos 5 vezes menor, ainda mais preferivelmente pelo menos 10 vezes menor, e de preferência pelo menos 20 vezes menor do que a concentração que seria necessária para originar um efeito biológico não relacionado com este.
Compostos
Num primeiro aspecto, a invenção proporciona novos inibidores da histona desacetilase.
Em particular, a invenção diz respeito a um inibidor de histona desacetilase com a fórmula (1);
ou a um seu sal aceitável do ponto de vista farmacêutico.
Composições Farmacêuticas
Num segundo aspecto, a invenção proporciona composições farmacêuticas que incluam um inibidor de 9 histona desacetilase de acordo com a invenção, e um veículo excipiente ou diluente aceitável do ponto de vista farmacêutico. Podem formular-se os compostos da invenção por qualquer um dos métodos que são bem conhecidos na técnica, e pode preparar-se para administração por uma via qualquer, incluindo, sem qualquer limitação, as vias parenteral, oral, sublingual, transdérmica, tópica, intranasal, intratraqueal, ou intra-rectal. Em determinadas aplicações preferidas, administram-se os compostos da invenção por via endovenosa, em instalações hospitalares. Em outras aplicações preferidas bem determinadas, a administração pode ser preferivelmente por via oral.
As características do veículo dependerão da via de administração. Tal como se utiliza neste documento, a expressão "aceitável do ponto de vista farmacêutico" significa um material não tóxico que é compatível com um sistema biológico tal como uma célula, uma cultura de células, um tecido, ou um organismo, e que não interfere com a eficácia da actividade biológica do(s) ingrediente(s) activo(s). Assim, as composições de acordo com a invenção podem conter, para além do inibidor, diluentes, cargas, sais, tampões, estabilizantes, solubilizadores, e outros materiais que são bem conhecidos na técnica. A preparação de formulações aceitáveis do ponto de vista farmacêutico está descrita por exemplo em Remington, Pharmaceutical Sciences, 18a Edição, editor A. Gennaro, Mack Publishing Co., Easton, PA, 1990. 10
Tal como se utiliza neste documento, a expressão sais aceitáveis do ponto de vista farmacêutico refere sais que mantêm a actividade biológica pretendida dos compostos identificados acima, e exibem efeitos toxicológicos indesejáveis minimos, ou não os exibem. Incluem-se como exemplos desses sais, que a estes eles se limitem, sais de adição a ácidos formados com ácido inorgânicos (por exemplo, ácido clorídrico, ácido bromídrico, ácido sulfúrico, ácido fosfórico, ácido nítrico, e outros semelhantes), e sais formados com ácidos orgânicos tais como ácido acético, ácido oxálico, ácido tartárico, ácido succínico, ácido málico, ácido ascórbico, ácido benzóico, ácido tânico, ácido pamóico, ácido algínico, ácido poliglutâmico, ácido naftalenossulfónico, ácido naftalenodissulfónico, e ácido poligalacturónico. Também se podem administrar os compostos sob a forma de sais quaternários aceitáveis do ponto de vista farmacêutico e conhecidos dos especialistas da técnica, nos quais se inclui especificamente o sal de amónio quaternário com a fórmula -NR + Z-, em que R seja hidrogénio, alquilo, ou benzilo, e Z seja um contra-ião, incluindo cloreto, brometo, iodeto, -O-alquilo, toluenossulfonato, metilsulfonato, sulfonato, fosfato, ou um carboxilato (tal como benzoato, succinato, acetato, glicolato, maleato, malato, citrato, tartarato, ascorbato, benzoato, cinamoato, mandelato, benziloato, e difenilacetato).
Inclui-se no veículo ou diluente aceitável do ponto de vista farmacêutico uma quantidade suficiente do 11 composto activo para que o paciente receba uma quantidade eficaz do ponto de vista terapêutico sem que surjam efeitos tóxicos colaterais de monta no paciente tratado. Uma dose preferida do composto activo, para todos os estados mencionados acima, é de entre cerca de 0,01 e 300 mg/kg, preferivelmente 0,1 a 100 mg/kg por dia, mais em geral 0,5 a cerca de 25 mg por quilograma de massa corporal do paciente, por dia. Uma dosagem tópica típica variará entre 0,01-3 %, em peso, num veículo adequado. A gama de dosagem dos derivados aceitável do ponto de vista farmacêutico pode ser calculada com base no peso do composto de que derivam, que há que veicular. Quando o derivado exibir actividade ele próprio, pode estimar-se a dosagem tal como acima, recorrendo ao peso do derivado, ou de outros modos que são do conhecimento dos especialistas da técnica.
Inibição de Histona Desacetilase
Num terceiro aspecto, a invenção proporciona um medicamento para inibir a histona desacetilase numa células, incluindo um inibidor de histona desacetilase de acordo com a invenção. Uma vez que os compostos da invenção inibem a histona desacetilase, eles são úteis como ferramentas de investigação para o estudo in vitro do papel da histona desacetilase em processos biológicos. Para além disto, os compostos da invenção inibem selectivamente determinadas isoformas de HDAC. 12
Pode conseguir-se a medição da actividade enzimática de uma histona desacetilase utilizando metodologias conhecidas. Por exemplo, Yoshida et al.r J. Biol. Chem., 265: 17174-17179 (1990), descrevem a avaliação da actividade enzimática da histona desacetilase pela detecção de histonas acetiladas em células tratadas por tricoestatina A. Taunton et al.r Science, 272: 408-411 (1996), descrevem de modo semelhante métodos para medir a actividade enzimática da histona desacetilase utilizando HDAC-1 endógena e recombinante.
Em algumas concretizações preferidas, o inibidor de histona desacetilase interactua com, e diminui a actividade de, todas as histona desacetilases da célula. Noutras concretizações preferidas de acordo com este aspecto da invenção, o inibidor de histona desacetilase interactua com, e diminui a actividade de, apenas parte das histona desacetilases da célula. Em algumas concretizações preferidas, o inibidor interactua com, e diminui a actividade de, uma histona desacetilase (por exemplo a HDAC-1), mas não interactua com, nem diminui a actividade de, outras histona desacetilases (por exemplo, a HDAC-2, a HDAC-3, a HDAC-4, a HDAC-5, a HDAC-β, a HDAC-7, e a HDAC-8) . Tal como se descreve adiante, alguns inibidores de histona desacetilase especialmente preferidos são aqueles que interactuam com, e que diminuem a actividade de, uma histona desacetilase que se encontra envolvida na génese de tumores. Outros inibidores de histona desacetilase 13 preferidos interactuam com, e diminuem a actividade enzimática, de, uma histona desacetilase de fungos.
Preferivelmente, o medicamento de acordo com o terceiro aspecto da invenção provoca uma inibição da proliferação celular das células com que entra em contacto. A frase "inibindo a proliferação de células" é utilizada para denotar uma capacidade de um inibidor da histona desacetilase para retardar o crescimento de células com as quais entra em contacto, em comparação com a de células com as quais não entra em contacto. Pode fazer-se uma avaliação da proliferação de células contando as células com as quais houve contacto e as células com as quais não houve contacto, recorrendo a um Contador de Células Coulter (Coulter, Miami, FL) ou a um hematocitómetro. Quando as células fazem parte de um crescimento em fase sólida (por exemplo um tumor sólido, ou um órgão), uma tal avaliação da proliferação celular pode ser feita medindo o crescimento com um nónio e comparando as dimensões dos crescimentos das células em contacto com o das células que não estiveram em contacto.
Preferivelmente, atrasa-se o crescimento das células em contacto com o inibidor em pelo menos 50 %, em comparação com o crescimento das células que não estiveram em contacto. Mais preferivelmente, inibe-se a proliferação celular em 100 % (isto é, as células em contacto não aumentam de número). De preferência, a frase "inibindo a proliferação de células" inclui uma diminuição do número ou 14 da dimensão das células em contacto, em comparação com os de células que não entraram em contacto. Deste modo, um inibidor de histona desacetilase de acordo com a invenção que iniba a proliferação de células nas células com que entra em contacto pode induzir a célula com a qual contacta a sofrer um atraso no crescimento, a sofrer uma paragem do crescimento, a sofrer uma morte celular programada (isto é, uma apoptose), ou a sofrer uma morte celular necrótica. A capacidade de inibição da proliferação de células manifestada pelos inibidores de histona desacetilase de acordo com a invenção permite a sincronização de uma população de células que crescem de forma assíncrona. Por exemplo, podem utilizar-se os inibidores de histona desacetilase da invenção para parar, nas fases G1 ou G2 do ciclo celular, uma população de células não neoplásicas cultivadas in vitro. Uma sincronização deste tipo permite, por exemplo, a identificação do gene e/ou dos produtos genéticos expressos durante as fases G1 ou G2 do ciclo celular. Uma tal sincronização de células em cultura também pode ser útil para testar a eficácia de um novo protocolo de transfecção, com o qual haja uma variação da eficiência da transfecção e que evidencie dependência em relação à fase especifica do ciclo celular que se vai transfectar. A utilização dos inibidores de histona desacetilase da invenção permite a sincronização de uma população de células, ajudando portanto na detecção de um aumento da eficiência da transfecção. 15
Em algumas concretizações preferidas, a célula que sofre o contacto é uma célula neoplásica. A expressão "célula neoplásica" é utilizada para denotar uma célula que apresenta um crescimento celular aberrante. Preferivelmente, o crescimento celular aberrante de uma célula neoplásica é um crescimento celular incrementado. Uma célula neoplásica pode ser uma célula hiperplásica, uma célula que apresente falta de inibição do crescimento por contacto in vitro, uma célula de tumor benigno que seja incapaz de originar metástases in vivo, ou uma célula cancerosa que seja capaz de originar metástases in vivo e que possa vir a recorrer após uma tentativa para a sua remoção. A expressão "génese de tumor" é utilizada para referir a indução da proliferação celular que leva ao desenvolvimento de um crescimento neoplásico. Em algumas concretizações, o inibidor de histona desacetilase induz uma diferenciação celular na célula com a qual entra em contacto. Deste modo, uma célula neoplásica, quando entra em contacto com um inibidor de histona desacetilase, pode ser induzida a sofrer uma diferenciação, da qual resulte a produção de uma célula filha não neoplásica que seja mais avançada do ponto de vista filogenético do que a célula que sofreu o contacto.
Em algumas das concretizações preferidas, a célula que sofre o contacto faz parte de um animal. Deste modo, a invenção proporciona um medicamento para tratar uma doença ou um estado que envolvam proliferação celular num 16 animal, incluindo a administração ao animal que necessite de um tal tratamento, de uma quantidade eficaz do ponto de vista terapêutico de um inibidor de histona desacetilase da invenção. Preferivelmente, o animal é um mamífero, mais preferivelmente um mamífero domesticado. De preferência o animal é um ser humano.
Pretende-se que a expressão "doença ou estado envolvendo proliferação celular" se refira a qualquer estado caracterizado por um crescimento aberrante de células, preferivelmente uma proliferação celular anormalmente aumentada. Incluem-se como exemplos de tais doenças de proliferação celular, sem que elas se limitem a estas, o cancro, a restenose, e a psoríase. Em concretizações especialmente preferidas, a invenção proporciona um método para inibir a proliferação de células neoplásicas num animal, que inclua administrar-se a um animal que tenha presente no seu corpo pelo menos uma célula neoplásica, uma quantidade eficaz do ponto de vista terapêutico de um inibidor de histona desacetilase da invenção.
Sabe-se o facto de alguns dos compostos da invenção têm actividade inibitória de histona desacetilase proveniente de protozoários. Deste modo, a invenção também proporciona um método para tratar ou para impedir uma doença ou infecção com protozoários, que inclui administrar-se a um animal que necessite de um tal tratamento uma quantidade eficaz do ponto de vista 17 terapêutico de um inibidor de histona desacetilase da invenção. Preferivelmente o animal é um mamifero, mais preferivelmente um ser humano. Preferivelmente, o inibidor de histona desacetilase utilizado de acordo com esta concretização da invenção inibe uma histona desacetilase de protozoários mais fortemente do que inibe histona desacetilases de mamíferos, em especial histona desacetilases de seres humanos. A invenção presente proporciona também um medicamento para tratar uma doença ou uma infecção devida a fungos, que inclui administrar-se a um animal que necessite de um tal tratamento uma quantidade eficaz do ponto de vista terapêutico de um inibidor de histona desacetilase da invenção. Preferivelmente o animal é um mamifero, mais preferivelmente um ser humano. Preferivelmente, o inibidor de histona desacetilase que se utiliza de acordo com esta concretização da invenção apresenta uma actividade de inibição de histona desacetilase de fungos maior do que a sua actividade de inibição de histona desacetilases de mamíferos, em especial histona desacetilases de seres humanos.
Pretende-se que a expressão "quantidade eficaz do ponto de vista terapêutico" signifique uma dosagem suficiente para provocar a inibição da actividade da histona desacetilase nas células do sujeito, ou uma dosagem suficiente para inibir a proliferação de células ou para induzir a diferenciação de células, no sujeito. A 18 administração pode ser feita por uma via qualquer, incluindo, sem limitação, as vias parentérica, oral, sublingual, transdérmica, tópica, intranasal, intratraqueal, ou intra-rectal. Em determinadas concretizações especialmente preferidas, administram-se os compostos da invenção por via endovenosa num ambiente hospitalar. Em algumas das outras concretizações preferidas, pode ocorrer preferivelmente uma administração pela via oral.
Quando é administrado por via sistémica, o inibidor de histona desacetilase é administrado preferivelmente a uma dosagem suficiente para que se atinja um teor de inibidor no sangue de entre cerca de 0,01 μΜ e cerca de 100 pm, mais preferivelmente de entre cerca de 0,05 μΜ e cerca de 50 μΜ, ainda mais preferivelmente de entre cerca de 0,1 μΜ e cerca de 25 μΜ, e mesmo ainda mais preferivelmente de entre cerca de 0,5 μΜ e cerca de 25 μΜ. Para uma administração localizada, podem ser eficazes concentrações muito inferiores, e podem ser toleráveis concentrações muito superiores. Um especialista da técnica entenderá que a dosagem do inibidor de histona desacetilase necessária para se obter um efeito terapêutico que varia consideravelmente consoante o tecido, o órgão, ou o animal ou paciente que se pretenda especificamente tratar.
Em algumas das concretizações especificas do terceiro aspecto da invenção, o tratamento inclui também levar-se ao contacto a célula e um oligonucleótido de 19 sentido reverso que inibe a expressão de uma histona desacetilase. A utilização do conjunto de um inibidor a nivel de ácido nucleico (por exemplo um oligonucleótido de sentido reverso) e um inibidor a nivel proteico (isto é, um inibidor da actividade enzimática da histona desacetilase), origina um efeito inibidor melhorado, diminuindo deste modo as quantidades de inibidores que são necessárias para se obter um efeito inibidor determinado em comparação com as quantidades que são necessárias quando se utiliza qualquer um deles individualmente. Os oligonucleótidos de sentido reverso de acordo com este aspecto da invenção são complementares de regiões do ARN ou do ADN de dupla cadeia, que codificam para HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC7, e/ou HDAC-8 (veja-se, por exemplo, o Número de Acessão U50079 no GenBank para HDAC-1, o Número de Acessão U31814 no GenBank para HDAC-2, e o Número de Acessão U75697 no GenBank para HDAC-3).
Para os efeitos da invenção, o termo "oligonucleótido" inclui polímeros de dois ou mais resíduos de desoxi-ribonucleósidos, de ribonucleósidos, ou de ribonucleósidos substituídos em 2' , ou uma qualquer combinação de todos estes. Preferivelmente, esses oligonucleótidos têm entre cerca de 6 e cerca de 100 resíduos de nucleósido, mais preferivelmente entre cerca de 8 e cerca de 50 resíduos de nucleósido, e de preferência entre cerca de 12 e cerca de 30 resíduos de nucleósido. Os resíduos de nucleósido podem ser acoplados uns aos outros por qualquer das numerosas ligações conhecidas entre 20 nucleósidos. Incluem-se nestas ligações entre nucleósidos, sem limitação, ligações fosforotioato, fosforoditioato, alquilfosfonato, alquilfosfonotioato, fosfotriéster, fosforamidato, siloxano, carbonato, éster carboximetilico, acetamidato, carbamato, tioéter, fosforamidato em ponte, metilenofosfonato em ponte, fosforotioato em ponte e sulfona entre nucleósidos. Em algumas concretizações preferidas, estas ligações entre nucleósidos podem ser ligações de fosfodiéster, fosfotriéster, fosforotioato, ou fosforamidato, ou combinações delas. O termo oligonucleótido também inclui polímeros dos que apresentem bases ou açúcares quimicamente modificados e/ou que apresentem substituintes adicionais, incluindo, sem qualquer limitação, grupos nucleófilos, agentes intercalantes, diaminas e adamantano.
Para os objectivos da invenção, o termo "ribonucleósido substituído em 2'" inclui ribonucleósidos nos quais o grupo hidroxilo na posição 2' da espécie pentose esteja substituído para dar um ribonucleósido substituído em 2'-O. Preferivelmente, uma substituição destas ocorre com um grupo alquilo inferior contendo 1-6 átomos de carbono, saturados ou insaturados, ou com um grupo arilo ou alilo com 2-6 átomos de carbono, em que estes grupos alquilo, arilo ou alilo possam ser não substituídos, ou possam ser substituídos, por exemplo com grupos halo, hidroxilo, trifluorometilo, ciano, nitro, acilo, aciloxilo, alcoxilo, carboxilo, carbalcoxilo, ou amino. O termo "ribonucleósido substituído em 2'" também 21 inclui ribonucleósidos nos quais o grupo 2'-hidroxilo seja substituído por um grupo amino ou por um grupo halo, preferivelmente fluoro.
Os oligonucleótidos de sentido reverso especialmente preferidos utilizados neste aspecto desta invenção, incluem oligonucleótidos quiméricos e oligonucleótidos híbridos.
Para os objectivos da invenção, um "oligonucleótido quimérico" refere-se a um oligonucleótido com mais do que um tipo de ligação entre nucleósidos. Um exemplo preferido de um tal oligonucleótido quimérico é um oligonucleótido quimérico que inclua uma região fosforotioato, fosfodiéster ou fosforoditioato, a qual contenha preferivelmente entre cerca de 2 e cerca de 12 nucleótidos, e uma região alquilfosfonato ou alquilfosfonotioato (veja-se por exemplo Pederson et al. Patentes U.S. Nos. 5.635.377 e 5.366.878). Preferivelmente, esses oligonucleótidos quiméricos contêm pelo menos três ligações consecutivas entre nucleósidos que são seleccionadas de entre as ligações fosfodiéster e fosforotioato, ou combinações destas.
Para os efeitos desta invenção, um "oligonucleótido híbrido" refere-se a um oligonucleótido com mais do que um tipo de nucleósido. Um exemplo preferido de um oligonucleótido híbrido inclui uma região de ribonucleótido ou de ribonucleótido substituído em 2', 22 preferivelmente contendo entre cerca de 2 e cerca de 12 nucleótidos substituídos em 2', e uma região de desoxi-ribonucleótido. Preferivelmente, um tal oligonucleótido híbrido contem pelo menos três ligações consecutivas entre desoxi-ribonucleósidos e contém também ribonucleósidos, ribonucleósidos substituídos em 2', preferivelmente ribonucleósidos substituído em 2'-0, ou combinações de todos estes (veja-se por exemplo, Metelev e Agrawal, Patente U.S. N°. 5.652.355). A sequência de nucleótidos exacta e a estrutura química de um oligonucleótido de sentido reverso utilizado na invenção pode ser variada, desde que o oligonucleótido mantenha a sua capacidade de inibir a expressão do gene que interessa. Isto determina-se facilmente testando se um determinado oligonucleótido de sentido reverso é activo. Incluem-se nos ensaios de determinação úteis para este propósito quantificar-se o mARN codificando para um produto do gene, um ensaio de análise por transferência Western do produto do gene, um ensaio de determinação da actividade para um produto genético activo, ou um ensaio de crescimento em agar mole, ou um ensaio de determinação de uma construção genética, ou um ensaio de avaliação in vivo de um crescimento de um tumor, todos os quais se encontram descritos em pormenor nesta especificação ou em Ramchandani et al. (1997) Proc. Natl. Acad. Sei. USA 94: 684-689.
Podem sintetizar-se de forma conveniente os oligonucleótidos de sentido reverso que se utilizam na invenção sobre um suporte sólido adequado, recorrendo a 23 técnicas químicas bem conhecidas, incluindo química de H-fosfonato, química de fosforamidito, ou uma combinação de química de H-fosfonato com química de fosforamidito (isto é, química de H-fosfonato para alguns ciclos e química de fosforamidito para outros ciclos). Incluem-se nos suportes sólidos adequados, quaisquer dos suportes sólidos utilizados para a síntese de oligonucleótidos em fase sólida, tais como vidro com dimensão de poros controlada (CPG) (veja-se por exemplo Pon, R.T. (1993) Methods in Molec. Biol. 20: 465-496).
Os oligonucleótidos especialmente preferidos têm sequências de nucleótido de entre cerca de 13 e cerca de 35 nucleótidos, que incluem as sequências de nucleótidos listadas na Tabela 1. Outras sequências de oligonucleótidos adicionais que são especialmente preferidos são as sequências de nucleótidos de entre cerca de 15 e cerca de 26 nucleótidos das sequências de nucleótidos listadas na Tabela 1.
Tabela 1
Oligo Alvo Número Acessão de Posição Nucleótido do „ Sequencia Posição no Gene HDAC1 AS1 HDAC1 Humana U50079 1585-1604 5'- GAAACGTGAGGGACTCAGCA- 3'-UTR HDAC1 AS2 HDAC1 Humana U50079 1565-1584 5'- GGAAGCCAGAGCTGGAGAGG- 3'-UTR HDAC1 MM HDAC1 Humana U50079 1585-1604 5'- GTTAGGTGAGGCACTGAGGA- 3' 3'-UTR HDAC2 AS HDAC2 Humana U31814 1643-1622 5'- GCTGAGCTGTTCTGATTTGG- 3'-UTR HDAC2 MM HDAC2 Humana U31814 1643-1622 5'- CGTGAGCACTTCTCATTTCC- 3' 3'-UTR HDAC3 HDAC3 AF039703 1276-1295 5'- 3'-UTR 24
Oligo Alvo Número Acessão de Posição Nucleótido do „ Sequencia Posição no Gene AS Humana CGCTTTCCTTGTCATTGACA- HDAC3 MM HDAC- Humana AF039703 1276-1295 3 5'- GCCTTTCCTACTCATTGTGT- 3' 3'-UTR HDAC4 AS1 HDAC4 Humana AB006626 514-33 5- GCTGCCTGCCGTGCCCACCC- 5'-UTR HDAC4 MM1 HDAC4 Humana AB006626 514-33 Ó 5 1 - CGTGCCTGCGCTGCCCACGG- 5'-UTR HDAC4 AS2 HDAC4 Humana AB006626 7710-29 5'- TACAGTCCATGCAACCTCCA- 3'-UTR HDAC4 MM4 HDAC4 Humana AB006626 7710-29 3 5'- ATCAGTCCAACCAACCTCGT- 3' 3'-UTR HDACS AS HDAC5 Humana AF039691 2663-2682 5'- CTTCGGTCTCACCTGCTTGG- 3' 3 ' -UTR HDAC6 AS HDAC6 Humana AJ011972 3791-3810 5'- CAGGCTGGAATGAGCTACAG- 3' -UTR HDAC6 MM HDAC6 Humana AJ011972 3791-3810 5'- GACGCTGCAATCAGGTAGAC- 3' 3 ' -UTR HDAC7 AS HDAC7 Humana AF239243 2896-2915 5'- CTTCAGCCAGGATGCCCACA-3 3'-UTR HDAC8 AS1 HDAC8 Humana AF230097 51-70 5'- CTCCGGCTCCTCCATCTTCC- 5'-UTR HDAC8 AS2 HDAC8 Humana AF230097 1328-1347 5'- AGCCAGCTGCCACTTGATGC- 3' 3 ' -UTR
Pretende-se que os exemplos seguintes contribuam para ilustrar melhor a invenção.
Exemplo 426 Síntese de N— (2—Amino—fenil)—4—[(4—piridin—3—il— pirimidin-2-ilamino)-metil]-benzamida 25
Intermediário 1
Esquema 66
Passo 1: Síntese de Éster metílico do ácido 4-guanidinometil-benzóico, Intermediário 1
Agitou-se a mistura de cloridrato do éster metilico do ácido 4-aminometil-benzóico (15,7 g, 77,8 mmol) em DMF (85,6 mL) com DIPEA (29,5 mL, 171,2 mmol) à temperatura ambiente, durante 10 minutos. Adicionou-se pirazole-l-carboxamidina*HCl (12,55 g, 85,6 mmol) à mistura reaccional, e depois agitou-se à temperatura ambiente durante 4 h para se obter uma solução limpida. Evaporou-se a mistura reaccional em vazio. Adicionou-se uma solução de NaHC03 (35 mL) para se obter uma boa suspensão. Filtrou-se a suspensão e lavou-se o bolo de filtração com água fria. Evaporaram-se as águas-mães à secura e em seguida filtrou- 26 se. Misturaram-se ambos os sólidos e voltou a suspender-se em H2O destilada (50 mL). Lavou-se então o bolo de filtração com as quantidades mínimas de H2O fria e de éter para se obterem 12,32 g de intermediário 1 sob a forma de um sólido cristalino branco (77 % de rendimento, M+l: 208 por MS).
Passo 2: Síntese de 3-Dimetilamino-l-piridin-3-il-propenona, Intermediário 2
Misturaram-se um com o outro 3-acetil-piridina (30,0 g, 247,6 mmol) e dimetilacetal da DMF (65,8 mL, 495,2 mmol), e depois aqueceu-se ao refluxo durante 4 h. Evaporou-se a mistura reaccional à secura e depois adicionaram-se 50 mL de éter dietílico para se obter uma suspensão castanha. Filtrou-se a suspensão para se obterem 36,97 g de um produto cristalino cor-de-laranja (85 % de rendimento, M+l: 177 por MS).
Passo 3: Síntese de Éster metílico do ácido 4-[(4-piridin-3-il-pirimidin-2-ilamino)-metil]-benzóico, Intermediário 3
Misturaram-se intermediário 1 (0,394 g, 1,9 mmol), intermediário 2 (0,402 g, 2,3 mmol) e peneiros moleculares (0,2 g, 4A, em pó, > 5 mícron), com álcool isopropílico (3,8 mL) . Aqueceu-se a mistura reaccional ao refluxo durante 5 h. Adicionou-se MeOH (50 mL) e depois aqueceu-se ao refluxo. Filtrou-se a solução turva através 27 de uma almofada de celite. Evaporaram-se as águas-mães à secura e triturou-se o resíduo com 3 mL de EtOAc. Filtrou-se a suspensão para se obterem 0,317 g de um sólido cristalino branco, Intermediário 3 (52 %, M+l: 321 por MS).
Passo 4: Síntese de N-(2-Amino-fenil)-4-[(4-piridin-3-il-pirimidin-2-ilamino)-metil]-benzamida
Misturou-se o Intermediário 3 (3,68 g, 11,5 inmol) com THF (23 mL), MeOH (23 mL) e H20 (11,5 mL) à temperatura ambiente. Adicionou-se LiOH (1,06 g, 25,3 mmol) à mistura reaccional. Aqueceu-se a mistura reaccional resultante até 40 °C de um dia para o outro. Adicionou-se uma solução de HC1 (12,8 mL, 2 N) para ajustar o pH=3 quando se arrefeceu a mistura até à temperatura ambiente. Evaporou-se a mistura à secura e lavou-se o sólido com a quantidade mínima de H20 quando se filtrou. Secou-se o bolo de filtração por liofilização para se obterem 3,44 g do ácido que é o composto em título (95 %, M+l: 307 por MS).
Dissolveu-se o ácido (3,39 g, 11,1 mmol) que é o composto em título, BOP (5, 679 g, 12,84 mmol) e o-Ph(NH2)2 (2,314 g, 21,4 mmol) numa mistura de DMF (107 mL) e Et2N (2,98 mL, 21,4 mmol). Agitou-se a mistura reaccional à temperatura ambiente durante 5 h e depois evaporou-se à secura. Purificou-se o resíduo por cromatografia rápida em coluna (de EtOAc puro a 5 % MeOH/EtOAc) e concentraram-se as fracções com interesse. Triturou-se o produto final com EtOAc para se obterem 2,80 g do produto em título (66 %, 28 MS + 1 : 5 ! 97 por MS) . RMN de XH 1 [400 MH z, DMSO '-D6) δ (ppm) : 9, 57 (s , 1H), 9,22 (s , 1H) , 8,6 ,6 (d, J= 3, 5 Hz, 1H) , 8, 39 (d, J= 5,1 Hz, 2H) , 8,00 (t, J = 6 ,5 Hz , 1H) , 7, 90 (d, J= 8,2Hz, 2H) , 7, 50 (m, 3H) , 7,25 (d, J = 5,1 Hz, 1H) , 7, 12 (d, J = = v, 4 Hz :, 1H), 6, 94 (dd, J = 7, 0, 7,8 Hz, 1H) , 6, 75 (d, J = = 8, 2 Hz :, 1H), 6, 57 (dd, J = 7, 0, 7,8 Hz, 1H) , 4, 86 (s, 2H) , 4 ,64 (d, J = 5,9 Hz, 2H).
Exemplo de Avaliação 1
Inibição da Actividade Enzimática da Histona Desacetilase 1.HDAC-1 Humana
Os inibidores de HDAC foram testados contra um enzima recombinante humano clonado HDAC-1 expresso e purificado a partir de um sistema de expressão de Bâculovirus em células de insecto. Para testar a desacetilase, incubaram-se 20.000 cpm do substrato de histona acetilado e marcado metabolicamente com [3H] (M.
Yoshida et al., J. Biol. Chem. 265(28): 17174-17179 (1990)), com 30 yg do hHDAC-1 clonado recombinante durante 10 minutos a 37 °C. Parou-se a reacção adicionando ácido
acético (0,04 M de concentração final) e HC1 (250 mM de concentração final). Extraiu-se a mistura com acetato de etilo e determinou-se o ácido acético [3H] que se extraiu por contagem de cintilação. Para os estudos de inibição, incubou-se previamente o enzima com os compostos a 4 °C 29 durante 30 minutos antes do início da determinação enzimática. Determinaram-se os valores de IC5o para os inibidores dos enzimas HDAC obtendo-se curvas de resposta à dose para compostos individuais, e determinando a concentração de inibidor da qual resultava cinquenta por cento da inibição máxima. Os valores de IC5o para os compostos relacionados estão apresentados na terceira coluna da Tabela 5.
2.Determinação de MTT
Plaquearam-se células HCT116 (a 2.000/poço) em placas de cultura de tecidos com 96 poços, no dia anterior ao do tratamento com composto. Adicionaram-se os compostos aos poços a diversas concentrações. Incubaram-se as células durante 72 horas a 37 °C numa incubadora, sob 5 % de CO2. Adicionou-se MTT brometo de (3-[4,5-dimetiltiazol-2-il]-2,5 difeniltetrazólio, Sigma) a uma concentração final de 0,5 mg/mL, e incubou-se com as células durante 4 horas antes de se adicionar um volume de tampão de dissolução (50 % de N, N-dimetilf ormamida, 20 % de SDS, pH 4,7) às células em cultura. Depois de uma incubação de um dia para o outro, determinou-se o corante dissolvido por uma leitura colorimétrica a 570 nM utilizando uma referência a 630 nM e um leitor de placas MR700 (Dynatech Laboratories Inc.). Transformaram-se os valores de DO em número de células de acordo com uma curva de crescimento padrão para a linha de células relevante. Determinou-se a concentração que diminui o número de células para 50 % do número de células tratadas 30 com solvente como sendo o IC5o para MTT. Apresentam-se estes valores de IC50 para compostos relacionados, na quarta coluna da Tabela 5. 3. Acetilação de Histona H4 em células inteiras por imunotransferências
Incubaram-se células T24 de cancro da bexiga humano que cresciam em cultura, com inibidores de HDAC, durante 16 h. Extrairam-se as histonas das células depois do período de cultura, tal como foi descrito por M. Yoshida et al. (J. Biol. Chem. 265(28): 17174-17179 (1990)).
Colocaram-se 20 g da proteína total de histona sobre SDS/PAGE e transferiu-se para membranas em nitrocelulose. Testaram-se as membranas com anticorpos policlonais específicos para histona H-4 acetilada (Upstate Biotech Inc.), e em seguida com anticorpos secundários conjugados com peroxidase de raiz forte (Sigma) . Levou-se a cabo uma determinação da Quimioluminiescência Incrementada (ECL) (Amersham) utilizando filmes da Kodak (Eastman Kodak). Quantificou-se o sinal de 3H por densitometria. Apresentam-se dados representativos na quinta coluna da Tabela 5. Apresentam-se os dados sob a forma da concentração eficaz para diminuir para 50 % o sinal de H-4 (EC50) .
Tabela 5a: Inibição da Histona Desacetilase 31
32
33
34Composto: 83
Estrutura ίHDAC-1: MTT H4Ac |Humana: 1 (HCT116) (T24) 1 IC50 j lICso (μΜ) EC50 (μΜ) (μΜ) ΝΗ, 1 N^Sí Λν^ν" Η ΎΊ Η 1 3 NHz fS i 5 5 ο U i = não disponível; 99 = >25 ..hEL.................... Tabela 5b
γ N^N Χ^ΝΓ^Ν" Η I π Η Γ2Ύύ
Exs Composto
Estrutura 135 1 204 136 I 207 137 1 210
HDAC-1 MTT ;H4Ac Humana (HCT116) (T24) IC50 IC50 (μΜ) EC50 (μΜ) 4 l na (μΜ) 5 0,4 j 0,6 2 3 I 0,9 1 35
36
37
Tabela 5c ;Εχ2; Composto Estrutura HDAC-1 MTT Humana (HCT116) IC50 (μΜ) I ! ICso (μΜ) 1 38 I Exs; Composto Estrutura HDAC-1 Humana IC50 (μΜ) | MTT (HCT116) ! ICso (μΜ) j I51 I ή o 22 4 ina i 15 5 L· í 0 0 i^Y^^nh ίςτ^Υ0 1 3 8 I3 j 5 9 I "VVnYi Q·™, I MeQAJ H U^NH OMe 0 12 22 na i |61b| 0 7 12 na i | 65 i xrV2 XJ H 4 37 na ; 1 71 ! ! H NH2 1 10 44 na i ; 72 I O iYW ζΫ"’ 1 MeCT^ ^ 16 21 na i 1 88 ! 0 jQTh "n ^ Ô"NH21 na >39 na i 1 90 i 0 ^Υ^'ΝΗ çn " çxm' l 10 5 5 39 I Exs; Composto Estrutura HDAC-1 Humana \ IC50 (μΜ) | MTT (HCT116) ! ICso (μΜ) j 191 0 r^Y^^NH onrθ'”** I i 4 | 7 1 5 i 92 i o.l fjx» cr ; 5 i 2 3 ; 93 i o QTsv CT 1 j 3 [ 1 1 5 | 94 i o cr^y cr : 3 [ 2 | 5 ) 95 0 ] Me0V^ fY^-NH N"Sr ^ym2 1 3 1 2 i 10 ) 96 0 i^Y^^NH »e.Nxr« n σΝΗζ i Me 4 | 3 25 i 97 i 0 CN^rw ^rNH2 i 10 1 12 na i 198; o XiX^NH nrr» or""· OCF 3 0,4 1 2 15 ) 99 0 (‘Υ'^'ΝΗ íXn^n^ f^Ym2 CFJJ-* U- I 2 | 5 I io ) 10 0 0 fYr^^NH ρχχ«Λ^ QTNH! F 4 1 3 5 40
42
Tabela 5d
43
44
46
47
48
49
50
51
Εχ2
Tabela 5e
Composto Estrutura HDAC-1
Humana IC50 (μΜ) MTT (HCT116) IC50 (μΜ) 52 52 Εχ2
Composto
Estruturai HDAC-1 i MTT
Humana (HCT116) I IC50 (μΜ) | IC50 (μΜ)
53
54
Tabela 5f ; Exs i Composto Estrutura ÍHDAC-1 Humana | ICso ! (μΜ) MTT (HCT116) IC50 (μΜ) i H4Ac | j(T24) i EC50 ; 1 (μΜ) 1 | 117 179 o ίιΐΊΡΊ ϊ f2 | i 0,3 | i | i 118 i 180 X ^ ^ ΐ Γ ΰ^1γΝ'γΧ1 Hj<T 0 \ 3 2 \ 5 1 | 119 i 181 CÒXu.^. N 0 ll Ί S o 'Lss? H,r . [ 0,5 0,4 [ 1 1 55
56
57
58
59
60
61
62
63 ; Exs i Composto Estrutura ÍHDAC-1 Humana [ ICso ! (μΜ) MTT H4Ac | (HCT116) (T24) IC50 (μΜ) ECso | (μΜ) | I 203 344 O ΒΥΐΛΓΤ5%ι p τ iv> 0 ^ | 0,5 0,2 | 1 | j 2 04 i 345 -··- - - :1-r ·“···; ··· xy °u | 0,4 0,8 \ i 1 I 205 346 o i Brr^rn h r W1 ll^VvS | 3 0,5 | <i | 20 6 347 0 VVSon h ^ N Π (Γ | 2 0, 6 | 2 1 2 07 I 348 o αΥΝ^'Ν/ΥΝ NH2 1 Hl | 2 0,3 | í (208 I 349 r'^ í j. ";· O *L^J | 13 1 1 3 i 2 0 9 i 350 FxY^ r^N^N^Y^i μ H2N | 2 1 | 5 1 211 ! 352 ! \=X Ν' *iy O | 16 9 1 212 ! 353 /0'N N “LJL· h JT2 O K^fJ 1 3 10 64Exs Composto
Estrutura 213 1 354
HDAC-1 MTT H4AC Humanai(HCT116) (T24) ICso jlCso (μΜ) EC50 (μΜ) (μΜ) LO LO \—1 214 1 355 215 1 356 216 1 357 217 1 358 218 | 359 219 1 3 60 220 1 361 221 1 3 62
65
66
67
68
69
70
71
72
73
75
76
77
78
79
Exemplo de Determinação 2
Efeitos Antineoplásicos dos inibidores de Histona Desacetilase sobre Xenotransplantes de Tumores Humanos In Vivo
Injectou-se por via subcutânea em murganhos nus fêmea BALB/c com oito a dez semanas de idade (Taconic Labs, Great Barrington, NY) , na zona do flanco, 2 x 106 células de carcinoma colo-rectal humano HCT116 previamente acondicionadas. 0 acondicionamento prévio destas células foi levado a cabo submetendo-as a um mínimo de três transplantes consecutivos na mesma estirpe de murganhos nus. Em seguida, retiram-se fragmentos do tumor com cerca de 30 mg, os quais se implantam por via subcutânea em murganhos, na área do flanco esquerdo, sob anestesia com Forene (Abbott Labs, Genebra, Suíça). Quando os tumores atingiam um volume médio de 100 mm3, tratavam-se os murganhos diariamente por injecção por via endovenosa, subcutânea ou intraperitoneal, com uma solução do inibidor de histona desacetilase num veículo apropriado, tal como PBS, DMSO/água, ou Tween 80/água, a uma dose inicial de 10 mg/kg. A dose óptima de inibidor de HDAC foi estabelecida em experiências de dose-resposta, de acordo com protocolos padrão. Calculou-se o volume do tumor em dias alternados após a infusão, de acordo com métodos padrão (por exemplo, Meyer et al., Int. J. Câncer 43: 851-856 (1989)). O tratamento com os inibidores de HDAC de acordo com a 80 invenção provocou uma diminuição significativa do peso e do volume do tumor, em relação a controlos tratados apenas com veiculo (isto é, sem inibidor de HDAC). Para além disto, quando se mediu o teor de acetilação da histona verificou-se que ele era significativamente maior em relação aos dos controlos. Apresentam-se dados para compostos seleccionados, na Tabela 6. A FIG. 1 ilustra o conjunto dos resultados experimentais obtidos para o composto 106, que inibe em 80 % o crescimento do tumor. As Figs. 2-10 ilustram os resultados obtidos com mais compostos testados.
Tabela 6 :: u:::::::::::: ν.·1·.·1·1·1·1·1·1·1·.·1
Actividade Antitumoral no Modelo de HCT 116 Colo-Rectal
Composto : ::v:vavav:í:í:v:vavaí:í:í:í:í:í:í:í 106 SSSélví 126 va-:-:-:-:-:- 9 1avavaí:1:1:v:v:v:v- ::v:vavav:í:í:vavav: 87 157 167 15 168 16 Α::ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ι:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ 154 1:111:1:1:1:1:1:.:.:.:.:.: I 98 !:i:i:i:i:.:.:.:.:.:.:i:i:i:i:.:.:.:.:. Ia: 2 0 m
In Vivo va-:-:-:-:-:-:-:-:-:-:-:-:-:-:-:-:-:-:-:-:-! % de Inibição do Crescimento do Tumor AVAVAVAVAVAVAVAVAVAVAVAVIVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVAVVA 80a 62£ íKÍSSíSSSSvS^^ 51£ 30£ 66a 58a 2 6b 1:1:1:1:-:1 2 6£ -b :1:1:1:1:::1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:::1:::1:-: >b 50 ::!:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:::ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:ΐ:::ΐ:1 23a 52a 1. P· 1.:.:.:.:.:.:.:.:1:1:1:1:1:1:.:.:.:.:.:.:.:.:. 81
Actividade Antitumoral no Modelo de HCT 116 Colo-Rectal
In Vivo
Composto % de Inibição do Crescimento do Tumor : 40 mg/kg i.p.
Tabela 7
Efeitos Antineoplásicos de Inibidores de Histona í Desacetilase em Modelos de Xenotransplante em Murganhos | Nus % de Inibição do Crescimento Tumoral composto A 549 (p.o.) SW4S ! (PO.) A 549 i (i-P.) HCT 116 i (i.p.) i SW 48 (i.p.) ( 10 6 40 % (70 i mg/kg) |16 % (60 mg/kg) ! - I 164 !42 % (70 ímg/kg) 62 % (60 mg/kg) - 37 % (20 | ! mg/kg) 99 % (25 mg/kg) i 22 8 145 % (70 25 % (60 | 64 % (20 i | 45 % (20 | 68 % (20 1 img/kg) mg/kg) | mg/kg) ; mg/kg) mg/kg) 424b 67 % (50 !78 % (30 :j 60 % (50 í77 % (75 | 68 % (25 | ;i mg/kg) ; mg/kg) ) mg/kg) ; mg/kg) mg/kg) |
Exemplo de Determinação 3
Efeito Antineoplásico Combinado de Inibidores de Histona Desacetilase e Oligonucleótidos de Sentido Reverso para Histona Desacetilase Sobre Células de Tumor In Vivo 82 A razão de ser deste exemplo é a de ilustrar a capacidade da utilização em conjunto de um inibidor de histona desacetilase e de um oligonucleótido de sentido reverso para histona desacetilase , para aumentar a inibição do crescimento do tumor num mamifero. Preferivelmente, o oligonucleótido de sentido reverso e o inibidor de HDAC inibem a expressão e a actividade da mesma histona desacetilase.
Tal como se descreveu no Exemplo 12 6, tratam-se diariamente murganhos portadores de tumores HCT116 implantados (volume médio de 100 mm3) com preparações contendo entre cerca de 0,1 mg e cerca de 30 mg por kg de massa corporal, de oligonucleótido de sentido reverso para histona desacetilase, em soro salino. Trata-se diariamente um segundo grupo de murganhos com preparações aceitáveis do ponto de vista farmacêutico contendo entre cerca de 0,01 mg e cerca de 5 mg por kg de massa corporal, de inibidor de HDAC.
Alguns murganhos recebem tanto o oligonucleótido de sentido reverso como o inibidor de HDAC. Destes murganhos, um subconjunto pode receber o oligonucleótido de sentido reverso e o inibidor de HDAC em simultâneo por via endovenosa pela veia da cauda. Outro subconjunto pode receber o oligonucleótido de sentido reverso pela veia da cauda, e o inibidor de HDAC por via subcutânea. Um outro subconjunto ainda pode receber tanto o oligonucleótido de sentido reverso como o inibidor de HDAC por via subcutânea. 83
De igual forma estabelecem-se subconjuntos de murganhos de controlo que não recebem qualquer tratamento (isto é, apenas soro salino) , aos quais se administra um oligonucleótido de sentido reverso que no diga respeito a HDAC, um composto de controlo que não iniba a actividade de histona desacetilase, e um oligonucleótido de sentido reverso que não diga respeito a HDAC em conjunto com um composto de controlo.
Mede-se o volume de tumor com nónios. 0 tratamento com o oligonucleótido de sentido reverso e com o inibidor da proteína histona desacetilase provoca uma diminuição significativa do peso e do volume do tumor, em relação aos controlos.
Lisboa, 5 de Maio de 2010.
Claims (6)
1 REIVINDICAÇÕES 1. Um inibidor de histona desacetilase com a fórmula (1):
ou um seu sal aceitável do ponto de vista farmacêutico.
2. Uma composição que inclua um composto de acordo com a reivindicação 1 e um veiculo aceitável do ponto de vista farmacêutico.
3. A utilização do composto da reivindicação 1 para a produção de um medicamento para inibir a histona desacetilase numa célula.
4. A utilização da composição da reivindicação 2 para a produção de um medicamento para inibir a histona desacetilase numa célula. Lisboa, 5 de Maio de 2010. 1 Actividade antitumoral de Inibidores de HDAC com Pequenas Moléculas MetilGene no Modelo de Tumor Colo-Rectal Humano CT116 1 Volume do Tumor
mi Inibição do Crescimento de Tumor de Cancro do Pulmão Humano A549 pelo Composto 106, Após Administração Intraperitoneal
Dias 2 Inibição do Crescimento de Tumor de Cancro Colo-Rectal Humano HCT116 pelo Composto 164, Após Administração Intraperitoneal Volume do Tumor
Veículo Composto 104,20 mg/kg, IP Inibição do Crescimento de Tumor de Cancro Pancreático Humano Panc-1 pelo Composto
228, Após Administração Oral
Dias - 3 - Inibição do Crescimento de Tumor de Cancro Colo-Rectal Humano HCT116 pelo Composto 311, Após Administração Intraperitoneal
Inibição do Crescimento de Tumor de Cancro Pancreático Humano Panc-1 pelo Composto jfo 376, Após Administração Oral
4 Inibição do Crescimento de Tumor de Cancro do Pulmão Humano A549 pelo Composto 402, Após Administração Intraperitoneal 4
Inibição do Crescimento de Tumor de Cancro Pancreático Humano Panc-1 pelo Composto
421, Após Administração Oral Volume do Tumor, (mm3)
Composto 421, 60 mg/kg, P.O. Veículo Dias
8 5 Inibição do Crescimento de Tumor de Cancro do Pulmão Humano A549 pelo Composto 424b, Após Administração Intraperitoneal 5
Inibição do Crescimento de Tumor de Cancro do Pulmão Humano A549 pelo Composto 424b, Após Administração Oral Volume do Tumor, (mm3)
Dias de Tratamento 6 Inibição do Crescimento de Tumor de Cancro do Pulmão Humano A549 pelo Composto 570, Após Administração Intraperitoneal Volume do Tumor
Dias I-11
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CN100540547C (zh) | 2009-09-16 |
EP1590340B1 (en) | 2010-04-07 |
CA2515338C (en) | 2008-09-16 |
EP1590340A1 (en) | 2005-11-02 |
JP3908773B2 (ja) | 2007-04-25 |
KR100893804B1 (ko) | 2009-04-20 |
US7838520B2 (en) | 2010-11-23 |
MXPA05008246A (es) | 2005-10-05 |
ES2341857T3 (es) | 2010-06-29 |
KR20050098228A (ko) | 2005-10-11 |
US6897220B2 (en) | 2005-05-24 |
AU2004210016B2 (en) | 2009-10-08 |
CN1723207A (zh) | 2006-01-18 |
ATE463490T1 (de) | 2010-04-15 |
US20060058298A1 (en) | 2006-03-16 |
WO2004069823A1 (en) | 2004-08-19 |
DK1590340T3 (da) | 2010-07-19 |
JP2006514998A (ja) | 2006-05-18 |
BRPI0407195A (pt) | 2006-02-14 |
AU2004210016A1 (en) | 2004-08-19 |
US20040142953A1 (en) | 2004-07-22 |
DE602004026407D1 (en) | 2010-05-20 |
HK1087707A1 (en) | 2006-10-20 |
CA2515338A1 (en) | 2004-08-19 |
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