BRPI0608806A2 - compostos quìmicos, composição farmacêutica e uso de compostos quìmicos - Google Patents
compostos quìmicos, composição farmacêutica e uso de compostos quìmicos Download PDFInfo
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- BRPI0608806A2 BRPI0608806A2 BRPI0608806-6A BRPI0608806A BRPI0608806A2 BR PI0608806 A2 BRPI0608806 A2 BR PI0608806A2 BR PI0608806 A BRPI0608806 A BR PI0608806A BR PI0608806 A2 BRPI0608806 A2 BR PI0608806A2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
- C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/08—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
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Abstract
COMPOSTOS QUìMICOS, COMPOSIçãO FARMACêUTICA E USO DE COMPOSTOS QUìMICOS Compostos químicos obtidos por modelação molecular in silico, e cuja estrutura permite o bloqueio de a fosforilação mediante a interação de ditos compostos com o domínio de fosforilação ou se entorno nos substratos daenzima Caseína Quinase 2. A invenção compreende ademais as composições farmacêuticas que contêm ditos compostos e seu uso na preparação de medicamentos para o tratamento de enfermidades relacionadas com processos neoplásicos.
Description
"COMPOSTOS QUÍMICOS, COMPOSIÇÃO FARMACÊUTICA E USODE COMPOSTOS QUÍMICOS"
Campo da técnica
A presente invenção se enquadra dentro do campo dafarmacologia molecular e concretamente com a oncologia, especificamentecom compostos químicos obtidos por modelação molecular in silico com açãocitotóxica e efeito antitumoral ao bloquear o sítio de fosforilação descrito paraos substratos da enzima Caseína Quinase 2 (CK2) mediante interação diretaou indireta e as composições farmacêuticas que os contêm.
Estado da técnica anterior
A CK2 é uma enzima serina/treonina que está involucrada noincremento da proliferação celular e sua localização intracelular éfundamentalmente nuclear durante o processo de transformação maligna(Tawfic S., Yu S., Wang H., Faust R., Davis A., Ahmed K. (2001) Proteinkinase CK2 signal in neoplasia. Histol. Histopathol. 16:573-582). Além disso,algumas proteínas virais chaves na patogenia do Vírus da ImunodeficiênciaHumana (HIV) e do Vírus da Hepatite C (VHC) foram reportadas comosubstratos para CK2 (Meggio F., Marín O., Boschetti M., Samo S., Pinna LA.(2001) Mol Cell Biochem 227:145-151 ; Franck N., Le Seyec J., Guguen-Guillouzo Cl Erdtmann L. (2005) Hepatitis C viras NS2 protein isphosphorylated by the protein kinase CK2 and targeted for degradation to theproteasome. J Virol. 79:2700-2008)
Achados de diferentes grupos no mundo confirmaram aexistência de níveis elevados de CK2 em diversos tumores sólidos de origemepitelial em ordenes entre 3 e 7 vezes respeito ao tecido normal (Tawfic S.,Yu S., Wang H., Faust R., Davis A., Ahmed K. (2001) Protein kinase CK2signal in neoplasia. Histol Histopatol. 16:573- 582; Faust R.A., Gapany M., etal (1996) Elevated protein kinase CK2 activity in chromatin of head and necktumors: association with malignant transformation. Câncer Letters 101 :31-- 35), além do a atividade de fosforilação por esta enzima é um evento celularimportante na transformação maligna e constitui um marcador de progressãodo tumor (Seldin D.C., Leder P. (1995) Casein Kinase IIa transgene-inducedmurine lymphoma: relation to theileroiosis in cattle. Science 267:894-897).
Por outro lado, a sobre-expressão de CK2 em animais transgênicos leva àtumorigênese das glândulas mamárias através do incremento da cascata desinalização Wnt/beta-catenina nas células epiteliais mamárias (Landesman-Bollag E., Romien-Mourez R., et al (2001) Protein Kinase CK2 in mammarygland tumorigenesis. Oncogene 20:3247-3257). Achados recentes sugeriramtambém que a enzima CK2 desempenha um papel essencial em processoscomo a remodelação da cromatina (Barz T., Ackenmann K., Dubois G., EilsR., Pyerin W. (2003) Genome-wide expression screens indicate a global rolefor protein kinase CK2 in chromatin remodeling. J Cell Sei. 116:1563-1577) ea manutenção da viabilidade celular (Unger G. M., Davis A.T., Slaton J.W.,Ahmed K. (2004) Protein kinase CK2 as regulador of cell survival:implications for câncer therapy. Curr Câncer Drug Targets, 4:77-84). Alémdisso, de conotada implicação para o processo de desenvolvimento do câncerforam os achados que demonstram que a fosforilação mediada por CK2constitui um sinal forte para a proteção frente ao fenômeno de apoptose, razãopela qual se considera esta enzima como um mediador antiapoptótico nafisiologia celular (Ahmed K., Gerber D. A., Cochet C. (2002) Joining the cellsurvival squad: an emerging role for protein kinase CK2. Trends Cell Biol,12:226-229; Torres J., Rodriguez J., et al (2003) Phosphorylation- regulatedcleavage of the tumor suppressor PTEN by caspase-3: implications for thecontrol of protein stability and PTEN-protein interactions. J Biol Chem,278:30652- 60).
Sobre a base dos achados anteriormente descritos confirma-seque a fosforilação mediada por CK2 é um evento bioquímico que constitui umalvo potencial para a intervenção terapêutica do câncer e que inibidores de talevento, podem constituir candidatos com perspectivas para o tratamento destaentidade. Até o momento diferentes grupos no mundo desenvolveramestratégias para inibir a fosforilação mediada por CK2 com o uso de duasabordagens experimentais: a) A inibição direta da enzima, ou b) O bloqueiodo sítio de fosforilação dentro do domínio acídico descrito para os substratosde CK2. Em ambos procedimentos, os autores demonstraram o conceito deque a inibição do evento de fosforilação mediado por esta quinase leva àindução de apoptose de células tumorais que constituem resultados devalidação experimental de CK2 como alvo de interesse no desenvolvimentode fármacos para o tratamento do câncer.
Por exemplo, um inibidor direto da enzima como é o 4, 5, 6, 7-tetrabromobenzotriazol (TBB) foi comprovado como indutor de apoptose e dedegradação dependente de caspase em células JurKatt na faixa deconcentração micromolar (Ruzzene M., Penzo D., Pinna L. (2002) Proteinkinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) inducesapoptose and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HSl) in Jurkat cells. Biochem J., 364:41-47). Também,mediante a inibição da expressão da enzima empregando oligonucleotidosanti-sentido foi demonstrado um efeito apoptótico in vitro, assim como açãoantitumoral em um modelo experimental de câncer em ratos (Guo Cl Yu S.,et al. (2001) A potential role of nuclear matrix- associated protein kinase CK2in protection against drug-induced apoptosis in câncer cells. J Biol Chem,276:5992-5999; Slaton J.W., et al. (2004) Induction of apoptosis by antisenseCK2 in human prostate câncer xenograft model. Mol Câncer Res. 2:712-721).
Outros inibidores do sítio de união ao ATP foram descritos para a CK2 entreos quais se encontram derivados de antraquinonas, flavonóides e compostosderivados do azabenzimidazol halogenado (Sarno S., et al. (2002) Toward therational design of protein kinase casein kinase-2 inhibitors. PharmacolTherapeutics 93:159-168). Da mesma forma reportou-se a identificação deum inibidor seletivo da CK2 mediante ligação molecular de alto fluxo queresultou ser o ácido 5-oxo-5,6-di-hidroindol(l,2-a)quinazolin-7-il=acético(IQA) (Vangrevelinghe E., et ai. (2003) Biochemical and three-dimensional-structural study of the specific inhibition of protein kinase CK2 by [5-oxo-5,6-dihydroindolo-(l ,2- a)quinazolin-7-yl]acetic acid (IQA). J Med Chem.46:2556-2662). Tais compostos mostraram seu efeito inibidor da atividadeenzimática in vitro em valores de Concentração Inibidora 50 (CI50) na faixamicromolar porém, não se reportou evidências de eficácia antitumoral in vivode ditos inibidores de CK2 em modelos experimentais de câncer.
A outra abordagem descrita para interferir no processo defosforilação mediado por CK2 foi mediante o bloqueio do sítio defosforilação dentro do domínio acídico encontrado nos substratos destaenzima. O pedido de patente WO 03/054002 e o trabalho de Perea S. E., et al.(2004) Antitumor effect of a novel proapoptotic peptide impairing thephosphorylation by the protein kinase CK2. Câncer Res. 64:7127-7129,limitam-se a propor o uso de uma família de peptídeos cíclicos que bloqueiama fosforilação do substrato de CK2 in vitro e mostram citotoxicidade emcélulas tumorais e efeito antitumoral em modelos preclínicos de câncer.Todavia, os peptídeos descritos nestes documentos apresentam a limitação deque não são capazes de penetrar por si sós no interior da célula necessitandoassim da fusão com outro tipo de peptídeo com capacidade intrínsecapermeável. Em geral, os peptídeos comparados a moléculas pequenaspossuem problemas com a estabilidade in-vivo dentro da circulação, assimcomo com sua administração oral e/ou penetração celular, aspectos nos quaisas moléculas pequenas os superam (Ludger Wess, Isogenica: Improvingpeptides, Biocentury 25 de outubro de 2004). Outras limitações das formaspeptídicas como terapêuticos constituem seu rápido apagamento assim comoseu potencial capacidade imunogênica e o custo econômico por doseterapêutica, geralmente superior aos fármacos.Explicação da invenção
Tendo em conta as limitações dos peptídeos cíclicos descritoscomo possíveis agentes terapêuticos a presente invenção descreve, com efeito,pela primeira vez, moléculas químicas que inibem a fosforilação medianteinteração direta ou indireta com o sítio de fosforilação dos substratos paraCK2, assim como a indução de citotoxicidade e efeito antitumoral emmodelos experimentais de câncer. Os compostos químicos da invenção têmuma estrutura que lhes permite cumprir com um ou vários dos seguintesrequerimentos:
A: provoca a união dos compostos ao domínio de fosforilaçãoou seu entorno no substrato da CK2, bloqueando direta ou indiretamente aunião da enzima ao substrato.
B: provoca a união dos compostos ao domínio de fosforilaçãodo substrato da CK2, permitindo a união da enzima porém bloqueando diretaou indiretamente a transferência do grupo fosfato para a serina fosfo-receptora.
C: provoca a união dos compostos à proteína substrato daCK2, provocando uma mudança conformacional no domínio de fosforilação,seu entorno ou ambos, de forma direta ou indireta que impede a união da CK2ou a transferência do grupo fosfato à serina fosfo-receptora.
Desta forma estes compostos se caracterizamfundamentalmente por sua capacidade de inibição do evento bioquímico defosforilação mediado por CK2.
Em uma realização particular, a invenção se refere a moléculasquímicas as quais apresentam uma estrutura química definida pela ocorrência,em qualquer parte da molécula, de maneira consecutiva dos seguinteselementos, com as características de hibridização assinaladas, ligados entre si,agrupados nas seguintes cinco classes estruturais:
I.N-[C(sp2)]1A3-NII. N-[C(sp2)] ι>2-[C(sp3)] ι,2,3-N
III. N-[C(sp3)]1A3-N
IV. N-C(sp2)-[C(sp3)]1;2-C(sp2)-N
V. N-C(sp3)-[C(sp2)]12-C(sp3)-N
Compostos pertencentes a estas classes estruturais sãomostrados em seguida:
<formula>formula see original document page 7</formula>
(1Z)-3,5,5-trimethylcyclohex-2-en-1-one semicarbazone
<formula>formula see original document page 7</formula>
A/-(4-amino-2,6-dihydroxypyrimidin-5-yl)-/\/'-isopropylthiourea
<formula>formula see original document page 7</formula>
3-({[(2-carboxyethyl)amino]carbonyl}amino)propanoic acid
<formula>formula see original document page 7</formula>
1-(2-chloroethyl)-3-(cyanomethyl)urea<formula>formula see original document page 8</formula><formula>formula see original document page 9</formula>
1-fert-butyl-3-(2-chloroethyl)urea
<formula>formula see original document page 9</formula>
1 -(2-chloroethyl)-3-(1 -methyl-1 -phenylethyl)urea
<formula>formula see original document page 9</formula>
1-(2-chloroethyl)-3-[1,1-dimethyl-2-(methylsulfonyl)ethyl]urea
<formula>formula see original document page 9</formula>
HN NH2 (2Z)-1-phenoxyacetone thiosemicarbazone
<formula>formula see original document page 9</formula>
{[({[(aminoacetyl)amino]acetyl}amino)acetyl]amino}acetic acid<formula>formula see original document page 10</formula><formula>formula see original document page 11</formula><formula>formula see original document page 12</formula>2-amino-4-{[(benzyloxy)carbonyl]amino}-4-oxobutanoic acid
<formula>formula see original document page 13</formula>
2-{[cyano(phenyl)methyl]amino}benzamide
<formula>formula see original document page 13</formula>
S-(2-imino-2-[[2-( 1 -methy 1-1 H-benzimidazol-2-yl)ethyl]amino}ethyl) hydrogen thiosulfate
<formula>formula see original document page 13</formula>
2-amino-6-[(2-hydroxypropyl)amino]-5-nitropyrimidin^-ol
<formula>formula see original document page 13</formula>
3-[2-amino-6-(methylthio)-9H-purin-9-yl]-5-(hydroxymethyl)cyclopentane-1,2-diol<formula>formula see original document page 14</formula>
Estas moléculas foram descritas para esta função mediante amodelagem molecular exaustiva do sítio de fosforilação de consenso definidopara esta enzima. (Meggio F., Pinna L.A. (2003) One-thousand-and-onesustrates of protein kinase CK2. The FASEB J. 17:349-368) sua validação porligação molecular à proteína CK2 e a posterior análise por acoplamentomolecular massivo de uma base de dados de diversidade química gerada nolaboratório da requerente contendo aproximadamente um milhão e duzentosmil compostos.
A invenção também inclui qualquer variante homóloga doscompostos anteriores. Entende-se por variante homóloga qualquer moléculade natureza química similar ou não aos aqui descritos, cuja estrutura permitarealizar o mesmo efeito dos compostos aqui descritos, e seu resultado sejainibir a fosforilação dos substratos de CK2.
Em outra realização preferida da invenção, a composiçãofarmacêutica contém um ou mais dos compostos químicos ou seus saisfarmaceuticamente aceitáveis, assim como excipientes ou veículosfarmaceuticamente aceitáveis. Também é parte da presente invenção o usodos compostos químicos, para a manufatura de medicamentos para a inibiçãoda proliferação de células tumorais in vitro, in vivo ou em dispositivosassociados ao corpo e para o tratamento do câncer em seres vivos e outrasenfermidades onde a CK2 possua um papel patológico. As moléculasquímicas descritas serão definidas por sua capacidade de inibir a fosforilaçãoda seqüência mínima de aminoácidos S/T-X-X-E/D sendo X preferivelmentealgum aminoácido diferente do tipo Lisina ou Arginina, ainda que não sedescartem outras proteínas, que não possuem esta seqüência de consensoporém que também são fosforiladas por CK2, unem este tipo de compostos esua fosforilação se vê inibida por eles.
Para a definição dos compostos químicos descritos nainvenção realizou-se a modelagem molecular exaustiva do sítio defosforilação de consenso descrito para esta enzima (Meggio F., Pinna L.A.(2003) One-thousand-and-one sustrates of protein kinase CK2. The FASEB J.17:349-368) sua validação por ligação molecular à proteína CK2 e a posterioranálise por acoplamento molecular massivo de uma base de dados dediversidade química gerada no laboratório da requerente, contendo um milhãoe duzentos mil compostos. Os compostos com valores calculados de energiade união acima da média foram selecionados como positivos para o primeirociclo, aplicando- lhes uma segunda rodada de acoplamento com valores maisrestritivos de seleção e foram analisados para extrair as regularidadesestruturais, a estrutura química dos compostos selecionados no segundo ciclofoi otimizada para obter valores maiores de energia de união calculada. Taiscompostos foram sintetizados, purificados utilizando Cromatografia Liquida,depois analisados por Espectrometria de Massas e Ressonância MagnéticaNuclear assim como Espectrofotometria Infravermelha e finalmente avaliadosquanto a sua efetividade in vitro e in vivo.
De acordo com esta invenção, os compostos químicosdescritos são igualmente eficazes quanto à sua capacidade de inibir o eventode fosforilação por CK2. Os compostos químicos descritos na presenteinvenção produzem citotoxicidade de uma maneira dose-dependente emcélulas tumorais de origem humana sem necessidade de acoplamento aveículos de penetração intracelular. Estas evidências se correspondem comachados prévios que demonstram que as moléculas químicas são capazes porsi sós de penetrar no interior da célula e interagir com seus respectivos alvos(Meggio F, Pagano MA, Moro S, Zagotto G, Ruzzene M, Samo Sl Cozza G,Bain J, Elliott M, Deana AD, Brunati AM, Pinna LA (2004) Inhibition ofprotein kinase CK2 by condensed polyphenolic derivatives. An in vitro and invivo study. Biochemistry. 43:12931-12936). Da mesma forma resulta deinteresse que os valores de CI50 encontrados para os compostos químicos dainvenção nos ensaios de citotoxicidade in vitro se encontrem na faixananomolar. Estes resultados demonstram uma maior eficácia anticelular doscompostos químicos descritos na invenção com respeito aos peptídeoscíclicos previamente descritos como inibidores do domínio de fosforilação deCK2. Em concordância com os resultados in vitro, os compostos químicos dapresente invenção exercem um potente efeito antitumoral quando estes sãoadministrados tanto por via sistêmica como localmente. Da mesma forma,demonstrou-se que os compostos químicos da invenção exercem um efeitoantitumoral em doses tão baixas quanto 0,5 e 2 mg/kg, o que representa umaredução de 10 a 20 vezes da dose na qual os peptídeos cíclicos descritosanteriormente conseguem um efeito similar.
Breve descrição das Figuras
Figura 1: Efeito antitumoral de compostos químicos emmodelos de tumores humanos implantados em ratos
Exposição detalhada de modos de realização/Exemplos
A presente invenção é explicada através dos seguintesexemplos de realização:
Exemplo 1: Seleção dos compostos mediante modelagem molecular in silico.
Mediante o uso do modelo computacional desenvolvido apartir do acoplamento molecular massivo foi selecionado um grupo decompostos baseados em uma alta energia de interação calculada para ocomplexo ligando receptor como se mostra na tabela seguinte. Esta energiaaproximada é estimada tendo em conta uma análise exaustiva da conformaçãoe dos componentes energéticos utilizando um programa computacionaldesenvolvido no laboratório da requerente.Tabela 1: Energias de interação calculadas para o complexo ligando-receptor
<table>table see original document page 17</column></row><table>
Exemplo 2: Efeito dos compostos químicos descritos sobre a fosforilação deum substrato típico de CK2.
Este ensaio consiste em uma reação de fosforilação in vitroonde se usou como substrato a oncoproteína E7 do Virus Papiloma Humanotipo 16 (VPH-16) expressada em E. Coli como proteína de fusão a GlutationS-Transferase (GST). Posteriormente, a E7-GST foi purificada porcromatografia de afinidade usando Glutation-Sefarose (Pharmacia). Antes dareação enzimática, a E7-GST foi pré-incubada com diferentes concentraçõesdos compostos químicos mencionados na invenção durante uma hora a 37°C.
A mistura de reação é realizada em 50 μΐ de buffer Tris:HCL 25 mM pH 7,5,1 μΟΐ de 32P- γΑΤΡ, 100 μΜ ATP, 40 μΐ da resina que contém E7-GST, 0,2 MNaCl , 10 mM MgCl e 1 unidade da enzima CK2 (Promega). A reação éincubada a 37°C durante 40 minutos.Em seguida foram se realizadas trêslavagens da resina com 0,5 ml do buffer de reação e finalmente o nível defosforilação da E7-GST é analisado em uma eletroforese PAGE a 10%. Avisualização da proteína fosforilada foi realizada mediante a revelação deplacas de raios X previamente expostas com o gel seco. A quantificação dafosforilação de E7 foi realizada mediante análise de densitometria dasrespectivas placas. Os valores de CI50 foram estimados a partir dasrespectivas curvas dose-efeito. A CI50 representa a concentração que inibe50% da atividade enzimática. Paralelamente incluiu-se como controle decomparação no ensaio o peptídeo cíclico Pl5 reportado como inibidor do sítiode fosforilação dos substratos de CK2. Os resultados observados na Tabela 2indicam que os diferentes compostos químicos descritos nesta invenção sãoinibidores efetivos de um sítio de fosforilação típico da CK2 segundo osvalores de CI50 observados. Resulta interessante o fato de que as moléculasquímicas descritas na invenção mostram maior capacidade inibidora comrespeito ao peptídeo cíclico reportado previamente como inibidor do sítio defosforilação de CK2 que somente exerce seu efeito inibidor na faixamicromolar.
Tabela 2: Efeito inibidor da fosforilação de um substrato típico de CK2
<table>table see original document page 18</column></row><table><table>table see original document page 19</column></row><table>
Exemplo 3: Efeito dos compostos químicos descritos sobre o sítio deconsenso de fosforilação da CK2.
Este ensaio consiste em uma reação de fosforilação in vitroonde se usou como substrato a seqüência RRREEETEEE que representa odomínio de consenso otimizado para a fosforilação por CK2. Antes da reaçãode fosforilação, o peptídeo substrato foi incubado durante uma hora a 37°Ccom os diferentes compostos químicos descritos na invenção. Em seguida, amistura de reação foi realizada em 50 μΐ de buffer Tris: HCL 25 mM pH 7,5,1 μα de 32P- γΑΤΡ, 100 μΜ ATP, 2 mg/ml do peptídeo substrato, 0,2 MNaCl, 10 mM MgCl e 1 unidade da enzima CK2 (Promega). A reação foiincubada a 37°C durante 10 minutos. Em seguida aplicou-se 5 μΐ da reaçãoem papel de filtro Whatmann PE-81 e realizou-se quatro lavagens com 10mM de H3PO4 Finalmente mediu-se a radioatividade associada ao papel defiltro e a quantidade de cpm por amostra reflete diretamente a atividadeenzimática de CK2. Paralelamente incluiu-se como controle de comparaçãono ensaio o peptídeo cíclico Pl5 reportado como inibidor do sítio defosforilação dos substratos de CK2. Os valores de CI50 que correspondem aoefeito inibidor foram estimados das respectivas curvas doses-efeito. A CI50representa a concentração que inibe 50% da atividade enzimática. Osresultados deste exemplo dados na Tabela 3, demonstrarão que os compostosquímicos mencionados nesta invenção inibem eficientemente a fosforilaçãodo substrato de CK2 in vitro segundo os valores de CI50 observados.
Ademais, estes resultados indicaram uma maior eficácia inibidora dasmoléculas químicas reportadas na invenção com respeito ao peptídeo cíclicopreviamente reportado como inibidor do sítio de fosforilação de CK2.
Tabela 3: Efeito dos compostos químicos descritos sobre o sítio deconsenso de fosforilação de a CK2
<table>table see original document page 20</column></row><table><table>table see original document page 21</column></row><table>
Exemplo 4: Efeito dos compostos químicos da presente invenção sobrecélulas tumorais humanas.
Para este ensaio, as células H-125 procedentes de umCarcinoma de Pulmão humano a Células Não Pequenas (NSCLC) foramsemeadas em placas de 96 poços (Costar) a uma densidade de 2x104células/ml em meio Dulbecco (DMEM) (Gibco) suplementado com SoroFetal Bovino (Gibco). Ao cabo de 24 horas, os compostos químicos descritosna presente invenção foram adicionados ao meio de cultivo em uma faixa dedoses compreendida entre 0.5 e 100 nM. A incubação foi realizada por espaçode 72 horas a 370C em presença de CO2 a 5% e ao término da mesmaadicionou-se 20 μΐ de uma solução de MTS 1,90 mg/ml. As placas forammantidas 1 hora adicional nas mesmas condições de incubação e finalmenterealizou-se a leitura da absorbância a 492 nm. Os resultados são mostradoscomo porcentagem de crescimento dos controles sem compostos químicos eos valores de IC50 foram calculados a partir das respectivas curvas de doses-resposta (Tabela 4). Os resultados obtidos neste ensaio demonstram que oscompostos químicos da presente invenção têm efeito citotóxico sobre célulastumorais em cultivos in vitro. Ademais, demonstra-se a superioridade de taiscompostos quanto à eficácia citotóxica com respeito ao peptídeo cíclico Pl5previamente descrito como inibidor do sítio fosforilável dos substratos de CK2.Tabela 4: Efeito dos compostos químicos sobre células tumorais humanas
<table>table see original document page 22</column></row><table>
Exemplo 5: Efeito antitumoral dos compostos químicos da invenção emmodelos de tumores humanos implantados em ratos atímicos.
Nestes ensaios utilizou-se ratos desnudos BaIbC de sexofeminino entre 6 e 8 semanas de nascidos. Para a implantação do tumor nestemodelo inoculou-se 5 000 000 de células H-125 ressuspensas em 250 μΐ dePBS na região dorsal dos animais. Una vez que os tumores eram palpáveiscom um volume em torno de 50 mm , realizou-se a administração direta de200 μg dos compostos C32425, C33426 e C33427 de maneira consecutivadurante 5 dias. Como se pode observar na Figura 1, a administração doscompostos químicos é capaz de produzir uma resposta antitumoralsignificativa. Estes resultados evidenciam a eficácia antitumoral de moléculasquímicas inibidoras do sítio de fosforilação da CK2 em um modelo relevanteda oncologia experimental.
Claims (4)
1. Compostos químicos os quais bloqueiam a fosforilação porCaseína Quinase 2 (CK2) e com ação antineoplásica, caracterizados pelo fatode que cumprem com um ou vários dos seguintes requisitos:a. unem-se ao domínio de fosforilação ou a seu entorno nosubstrato da CK2, bloqueando direta ou indiretamente a união da enzima aosubstrato.b. impedem direta ou indiretamente a transferência do grupofosfato à serina fosfo-receptora.c. sua união à proteína substrato da CK2, gera uma mudançaconformacional no domínio de fosforilação, seu entorno ou ambos, de formadireta ou indireta, de acordo com o descrito em a e b.
2. Compostos químicos e suas variantes homólogas, de acordocom a reivindicação 1, caracterizados pelo fato de que a estrutura químicaestá definida pela ocorrência, em qualquer parte da molécula, de maneiraconsecutiva dos seguintes elementos ligados entre si e com as característicasde hibridização assinaladas e são selecionados de pelo menos um dosseguintes grupos:I. N-[C(sp2)]1A3-NII. N-[C(sp2)]U2-[C(sp3)]1,2,3-NIII. N-[C(sp3)]Uí3-NIV. N-C(sp2)-[C(sp3)] i,2-C(sp2)-NV. N-C(sp3)-[C(sp2)]lj2-C(sp3)-N
3. Composição farmacêutica para o tratamento deenfermidades onde a CK2 possua um papel patológico e outras relacionadascom processos neoplásicos, caracterizada pelo fato de que compreende um oumais dos compostos químicos ou seus sais farmaceuticamente aceitáveis,como definidos em qualquer uma das reivindicações 1 e 2 e excipientes ouveículos farmaceuticamente aceitáveis.
4. Uso de compostos químicos de acordo com qualquer umadas reivindicações 1 e 2, caracterizado pelo fato de que é para a manufaturade medicamentos para a inibição da proliferação de células tumorais in vitro,in vivo ou em dispositivos associados ao corpo e para o tratamento do câncerem seres vivos e outras enfermidades onde a CK2 possua um papelpatológico.
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US6962698B1 (en) * | 1998-02-17 | 2005-11-08 | Gamida Cell Ltd. | Methods of controlling proliferation and differentiation of stem and progenitor cells |
BR9914465A (pt) * | 1998-09-29 | 2001-10-09 | Gamida Cell Ltd | Métodos para controlar a proliferação e a diferenciação de células-tronco e células progenitoras e uma composição farmacêutica para induzir a diferenciação em uma população de células |
CU23225A1 (es) | 2001-12-20 | 2007-08-30 | Ct Ingenieria Genetica Biotech | PéPTIDOS PARA EL TRATAMIENTO DEL CáNCER ASOCIADO AL VIRUS PAPILOMA HUMANO (VPH) Y DE OTROS TUMORES EPITELIALES |
EP1718297A4 (en) * | 2004-01-09 | 2009-09-02 | Smithkline Beecham Corp | NEW CHEMICAL COMPOUNDS |
WO2006065724A2 (en) * | 2004-12-14 | 2006-06-22 | Regents Of The University Of Minnesota | Casein kinase 2 antisense therapy |
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2005
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- 2006-05-05 EP EP06753157.4A patent/EP1892245B1/en active Active
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Also Published As
Publication number | Publication date |
---|---|
CN101203522A (zh) | 2008-06-18 |
RU2007146169A (ru) | 2009-06-20 |
DK2474528T3 (da) | 2014-10-27 |
PT2474528E (pt) | 2014-10-28 |
CA2607298C (en) | 2014-12-09 |
EP2474528B1 (en) | 2014-09-24 |
JP5117377B2 (ja) | 2013-01-16 |
CN101203522B (zh) | 2011-06-08 |
ES2516240T3 (es) | 2014-10-30 |
US8748411B2 (en) | 2014-06-10 |
WO2006119713A2 (es) | 2006-11-16 |
WO2006119713A3 (es) | 2007-03-01 |
EP1892245B1 (en) | 2015-07-29 |
ZA200709692B (en) | 2008-11-26 |
CU23431B6 (es) | 2009-10-16 |
JP2008543735A (ja) | 2008-12-04 |
EP1892245A2 (en) | 2008-02-27 |
ES2550959T3 (es) | 2015-11-13 |
MY140530A (en) | 2009-12-31 |
MX2007014216A (es) | 2008-02-07 |
PT1892245E (pt) | 2015-11-12 |
DK1892245T3 (en) | 2015-11-02 |
CA2607298A1 (en) | 2006-11-16 |
AU2006246204A1 (en) | 2006-11-16 |
AU2006246204B2 (en) | 2012-04-19 |
KR20080008407A (ko) | 2008-01-23 |
AR057012A1 (es) | 2007-11-07 |
EP2474528A1 (en) | 2012-07-11 |
RU2404987C2 (ru) | 2010-11-27 |
US20090215730A1 (en) | 2009-08-27 |
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