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1.
Cancer Chemother Pharmacol ; 65(4): 707-17, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19649632

RESUMO

PURPOSE: The Aurora family of serine/threonine kinases (Aurora-A, Aurora-B, and Aurora-C) plays a key role in cells orderly progression through mitosis. Elevated expression levels of Aurora kinases have been detected in a high percentage of melanoma, colon, breast, ovarian, gastric, and pancreatic tumors. We characterized the biological and pharmacological properties of SNS-314, an ATP-competitive, selective, and potent inhibitor of Aurora kinases. METHODS: We studied the biochemical potency and selectivity of SNS-314 to inhibit Aurora kinases A, B, and C. The inhibition of cellular proliferation induced by SNS-314 was evaluated in a broad range of tumor cell lines and correlated to inhibition of histone H3 phosphorylation, inhibition of cell-cycle progression, increase in nuclear content and cell size, loss of viability, and induction of apoptosis. The dose and administration schedule of SNS-314 was optimized for in vivo efficacy in mouse xenograft models of human cancer. RESULTS: In the HCT116 human colon cancer xenograft model, administration of 50 and 100 mg/kg SNS-314 led to dose-dependent inhibition of histone H3 phosphorylation for at least 10 h, indicating effective Aurora-B inhibition in vivo. HCT116 tumors from animals treated with SNS-314 showed potent and sustained responses including reduction of phosphorylated histone H3 levels, increased caspase-3 and appearance of increased nuclear size. The compound showed significant tumor growth inhibition in a dose-dependent manner under a variety of dosing schedules including weekly, bi-weekly, and 5 days on/9 days off. CONCLUSIONS: SNS-314 is a potent small-molecule inhibitor of Aurora kinases developed as a novel anti-cancer therapeutic agent for the treatment of diverse human malignancies.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/prevenção & controle , Compostos de Fenilureia/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiazóis/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Aurora Quinase A , Aurora Quinase B , Aurora Quinase C , Aurora Quinases , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Feminino , Células HCT116 , Células HT29 , Células HeLa , Histonas/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Compostos de Fenilureia/química , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Tiazóis/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem Lett ; 16(3): 559-62, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16274992

RESUMO

Disulfide Tethering was applied to the active site of human caspase-1, resulting in the discovery of a novel, tricyclic molecular fragment that selectively binds in S4. This fragment was developed into a class of potent inhibitors of human caspase-1. Several key analogues determined the optimal distance of the tricycle from the catalytic residues, the relative importance of various features of the tricycle, and the importance of the linker.


Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Sítios de Ligação , Caspase 1/química , Catálise , Inibidores Enzimáticos/farmacologia , Humanos , Relação Estrutura-Atividade
3.
Artigo em Inglês | MEDLINE | ID: mdl-16511067

RESUMO

Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.


Assuntos
Inibidores de Caspase , Técnicas de Química Combinatória/métodos , Inibidores de Cisteína Proteinase/química , Sítios de Ligação/efeitos dos fármacos , Caspase 1/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/sangue , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/metabolismo , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Solubilidade
5.
Nat Biotechnol ; 21(3): 308-14, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12563278

RESUMO

Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.


Assuntos
Inibidores de Caspase , Caspases/química , Técnicas de Química Combinatória/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Células Jurkat/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Caspase 3 , Caspases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/classificação , Humanos , Células Jurkat/metabolismo , Espectrometria de Massas/métodos , Modelos Moleculares , Biblioteca de Peptídeos
6.
J Med Chem ; 45(23): 5005-22, 2002 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-12408711

RESUMO

The design, synthesis, and in vitro activities of a series of potent and selective small-molecule inhibitors of caspase-3 are described. From extended tethering, a salicylic acid fragment was identified as having binding affinity for the S(4) pocket of caspase-3. X-ray crystallography and molecular modeling of the initial tethering hit resulted in the synthesis of 4, which reversibly inhibited caspase-3 with a K(i) = 40 nM. Further optimization led to the identification of a series of potent and selective inhibitors with K(i) values in the 20-50 nM range. One of the most potent compounds in this series, 66b, inhibited caspase-3 with a K(i) = 20 nM and selectivity of 8-500-fold for caspase-3 vs a panel of seven caspases (1, 2, and 4-8). A high-resolution X-ray cocrystal structure of 4 and 66b supports the predicted binding modes of our compounds with caspase-3.


Assuntos
Ácido Aspártico/síntese química , Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Salicilatos/síntese química , Sulfonamidas/síntese química , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Benzoxazóis/síntese química , Benzoxazóis/química , Sítios de Ligação , Caspase 3 , Caspases/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Fluorenos/síntese química , Fluorenos/química , Humanos , Ligação Proteica , Salicilatos/química , Sulfonamidas/química , Tiofenos/síntese química , Tiofenos/química
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