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1.
J Med Chem ; 63(24): 15541-15563, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33264017

RESUMO

Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC50 of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC50 = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.


Assuntos
Fluorenos/química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/química , Animais , Sítios de Ligação , Carbazóis/química , Carbazóis/metabolismo , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Cães , Feminino , Fluorenos/metabolismo , Fluorenos/farmacologia , Fluorenos/uso terapêutico , Meia-Vida , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Camundongos , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Clin Cancer Res ; 24(11): 2559-2573, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29500275

RESUMO

Purpose: Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.Experimental Design: Here, we investigated immunocompetent orthotopic mouse models of glioblastoma treated with the potent CNS-penetrating IDO1 enzyme inhibitor, BGB-5777, combined with anti-PD1 mAb, as well as radiotherapy, based on our recent observation that tumor-infiltrating T cells directly increase immunosuppressive IDO1 levels in human glioblastoma, the previously described reinvigoration of immune cell functions after PD-1 blockade, as well as the proinflammatory effects of radiation.Results: Our results demonstrate a durable survival benefit from this novel three-agent treatment, but not for any single- or dual-agent combination. Unexpectedly, treatment efficacy required IDO1 enzyme inhibition in non-glioblastoma cells, rather than tumor cells. Timing of effector T-cell infiltration, animal subject age, and usage of systemic chemotherapy, all directly impacted therapy-mediated survival benefit.Conclusions: These data highlight a novel and clinically relevant immunotherapeutic approach with associated mechanistic considerations that have formed the basis of a newly initiated phase I/II trial for glioblastoma patients. Clin Cancer Res; 24(11); 2559-73. ©2018 AACR.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Radiação Ionizante , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacocinética , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Sinergismo Farmacológico , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/metabolismo , Análise de Sobrevida , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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