RESUMO
Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kß selectivity for two chemical series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kß. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores Enzimáticos/química , Modelos Moleculares , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzoxepinas/química , Benzoxepinas/farmacocinética , Benzoxepinas/farmacologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/química , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Camundongos , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Conformação Proteica , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Linhagem Celular , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Modelos Moleculares , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor.
Assuntos
Inibidores Enzimáticos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Tiofenos/farmacologia , Animais , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Feminino , Camundongos , Pirimidinas/química , Ratos , Serina-Treonina Quinases TOR , Tiofenos/químicaRESUMO
The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Tiofenos/farmacologia , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Classe Ib de Fosfatidilinositol 3-Quinase , Isoenzimas/antagonistas & inibidores , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR , Tiofenos/síntese química , Tiofenos/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110alpha with IC(50) < or = 10 nmol/L. Despite some differences in isoform selectivity, these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines, with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103, following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice, with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/kg b.i.d.) and PI-620 (25 mg/kg b.i.d.), respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103, PI-540, and PI-620 and exhibited 78% oral bioavailability in mice, with tumor exposure above 50% antiproliferative concentrations for >8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity, with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts, respectively. Together, these data support the development of GDC-0941 as a potent, orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.
Assuntos
Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Glioblastoma/tratamento farmacológico , Indazóis/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Tiofenos/administração & dosagem , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Glioblastoma/enzimologia , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases/metabolismo , Pirimidinas/farmacocinética , Serina-Treonina Quinases TOR , Tiofenos/farmacocinética , Tiofenos/farmacologia , Veias Umbilicais/citologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Sulfonamidas/farmacologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Indazóis/administração & dosagem , Indazóis/farmacocinética , Indazóis/uso terapêutico , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.
Assuntos
Resistência a Múltiplos Medicamentos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Pirimidinas/síntese química , Pirróis/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Animais , Área Sob a Curva , Disponibilidade Biológica , Transporte Biológico , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Daunorrubicina/metabolismo , Daunorrubicina/farmacologia , Sinergismo Farmacológico , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.
Assuntos
Resistência a Múltiplos Medicamentos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Pirimidinas/síntese química , Pirróis/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Animais , Área Sob a Curva , Disponibilidade Biológica , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ontogen is developing ONT-093 (formerly OC-144-093), a P-glycoprotein pump inhibitor, for the potential reversal of multidrug resistance in patients undergoing cancer chemotherapy. The compound is also being evaluated for its potential enhancement of the oral bioavailability of drugs that are P-glycoprotein substrates requiring either high dosage forms or intravenous administration, and for the potential improvement of central nervous system penetration of P-glycoprotein substrate drugs.
Assuntos
Resistência a Múltiplos Medicamentos , Imidazóis/uso terapêutico , Tecnologia Farmacêutica/métodos , Animais , Ensaios Clínicos como Assunto/estatística & dados numéricos , Resistência a Múltiplos Medicamentos/fisiologia , Humanos , Imidazóis/química , Imidazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tecnologia Farmacêutica/legislação & jurisprudênciaRESUMO
Several isoquinoline-based templates were identified from the studies of the conformational effects of the diketopiperazine structures for PAI-1 inhibition. Moderate to good activity was retained with the elimination of unattractive characteristics in the diketopiperazine template.
Assuntos
Piperazinas/síntese química , Inibidor 1 de Ativador de Plasminogênio/química , Dicetopiperazinas , Humanos , Concentração Inibidora 50 , Piperazinas/farmacologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
We have synthesized and evaluated a series of tetramic acid-based and hydroxyquinolinone-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). These studies resulted in the identification of several compounds which showed excellent potency against PAI-1. The design, synthesis and SAR of these compounds are described.
Assuntos
Hidroxiquinolinas/síntese química , Hidroxiquinolinas/farmacologia , Inibidor 1 de Ativador de Plasminogênio/síntese química , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Pirrolidinonas/química , Compostos Cromogênicos/química , Desenho de Fármacos , Avaliação de Medicamentos , Hidroxiquinolinas/química , Técnicas In Vitro , Estrutura Molecular , Inibidor 1 de Ativador de Plasminogênio/química , Relação Estrutura-AtividadeRESUMO
A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.