RESUMO
The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH.
Assuntos
Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Comunicação Parácrina/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/imunologia , Antineoplásicos/imunologia , Antineoplásicos/farmacocinética , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Células HT29 , Proteínas Hedgehog/imunologia , Humanos , Cinética , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Células NIH 3T3 , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Comunicação Parácrina/imunologia , Ligação Proteica/imunologia , Ratos Wistar , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Células Estromais/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Tiofenos/química , Tiofenos/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Linhagem Celular , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Pirrolidinonas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese químicaRESUMO
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirrolidinonas/farmacologia , 17-Hidroxiesteroide Desidrogenases/metabolismo , Inibidores Enzimáticos/química , Humanos , Pirrolidinonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC(50)<10nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.
