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1.
J Med Chem ; 45(18): 3905-27, 2002 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-12190313

RESUMO

High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.


Assuntos
Antineoplásicos/síntese química , Benzenoacetamidas , Quinases relacionadas a CDC2 e CDC28 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Oxazóis/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiazóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Técnicas de Química Combinatória , Cristalografia por Raios X , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , DNA Polimerase I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Modelos Moleculares , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fosforilação , Ligação Proteica , Proteína do Retinoblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia , Células Tumorais Cultivadas
2.
J Med Chem ; 47(7): 1719-28, 2004 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-15027863

RESUMO

N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.


Assuntos
Antineoplásicos/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Quinases relacionadas a CDC2 e CDC28/metabolismo , Linhagem Celular Tumoral , Sistema Livre de Células , Cristalografia por Raios X , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fosforilação , Ratos , Proteína do Retinoblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Transplante Heterólogo
4.
Bioorg Med Chem Lett ; 13(6): 1133-6, 2003 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-12643928

RESUMO

1H-Pyrazolo[3,4-b]pyridine 3 (SQ-67563) has been shown to be a potent, selective inhibitor of CDK1/CDK2 in vitro. In cells 3 acts as a cytotoxic agent with the ability to block cell cycle progression and/or induce apoptosis. The solid state structure of 3 bound to CDK2 shows 3 resides coincident with the ATP purine binding site and forms important H-bonding interactions with Leu83 on the protein backbone.


Assuntos
Quinases relacionadas a CDC2 e CDC28 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Bioensaio , Proteína Quinase CDC2/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Quinase 2 Dependente de Ciclina , Feminino , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
Bioorg Med Chem Lett ; 13(14): 2405-8, 2003 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-12824044

RESUMO

Structure-activity studies of 1H-pyrazolo[3,4-b]pyridine 1 have resulted in the discovery of potent CDK1/CDK2 selective inhibitor 21h, BMS-265246 (CDK1/cycB IC(50)=6 nM, CDK2/cycE IC(50)=9 nM). The 2,6-difluorophenyl substitution was critical for potent inhibitory activity. A solid state structure of 21j, a close di-fluoro analogue, bound to CDK2 shows the inhibitor resides coincident with the ATP purine binding site and forms important H-bonds with Leu83 on the protein backbone.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Trifosfato de Adenosina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Quinase 2 Dependente de Ciclina , Quinases Ciclina-Dependentes/química , Ligação de Hidrogênio , Indicadores e Reagentes , Leucina/química , Modelos Moleculares , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 14(11): 2973-7, 2004 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-15125971

RESUMO

N-Aryl aminothiazoles 6-9 were prepared from 2-bromothiazole 5 and found to be CDK inhibitors. In cells they act as potent cytotoxic agents. Selectivity for CDK1, CDK2, and CDK4 was dependent of the nature of the N-aryl group and distinct from the CDK2 selective N-acyl analogues. The N-2-pyridyl analogues 7 and 19 showed pan CDK inhibitory activity. Elaborated analogues 19 and 23 exhibited anticancer activity in mice against P388 murine leukemia. The solid-state structure of 7 bound to CDK2 shows a similar binding mode to the N-acyl analogues.


Assuntos
Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Leucemia/tratamento farmacológico , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Ligação Proteica , Relação Estrutura-Atividade , Tiazóis/síntese química , Resultado do Tratamento
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