RESUMO
Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity.
Assuntos
Antineoplásicos/administração & dosagem , Benzoatos/administração & dosagem , Ciclopropanos/administração & dosagem , Metilação de DNA/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Histona Desmetilases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/farmacologia , Benzoatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopropanos/farmacologia , Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Dados de Sequência Molecular , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.
Assuntos
Antineoplásicos/farmacologia , Diaminas/farmacologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Carga Tumoral/efeitos dos fármacos , Administração Oral , Animais , Antineoplásicos/síntese química , Glicemia/metabolismo , Linhagem Celular Tumoral , Diaminas/síntese química , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos SCID , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/síntese química , Proteínas Quinases S6 Ribossômicas/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Tiofenos/química , Animais , Cristalografia por Raios X , Descoberta de Drogas/métodos , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tienopiridinas , Tiofenos/síntese química , Tiofenos/farmacologiaRESUMO
AKT inhibitors containing an imidazopyridine aminofurazan scaffold have been optimized. We have previously disclosed identification of the AKT inhibitor GSK690693, which has been evaluated in clinical trials in cancer patients. Herein we describe recent efforts focusing on investigating a distinct region of this scaffold that have afforded compounds (30 and 32) with comparable activity profiles to that of GSK690693.
Assuntos
Oxidiazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Linhagem Celular , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Estrutura Secundária de Proteína/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-AtividadeRESUMO
The first total synthesis of (+/-)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Delta13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6alpha hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.