RESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Diaminas/farmacología , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Carga Tumoral/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos/síntesis química , Glucemia/metabolismo , Línea Celular Tumoral , Diaminas/síntesis química , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Ratones , Ratones SCID , Fosfohidrolasa PTEN/antagonistas & inhibidores , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/síntesis química , Proteínas Quinasas S6 Ribosómicas/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas/genética , Proteínas Quinasas S6 Ribosómicas/metabolismo , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.
Asunto(s)
Antineoplásicos/síntesis química , Glicina/análogos & derivados , Inhibidores de Proteínas Quinasas/síntesis química , Sulfonas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Disponibilidad Biológica , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , Trasplante HeterólogoRESUMEN
A novel series of AKT inhibitors containing 2,3,5-trisubstituted pyridines with novel azaindazoles as hinge binding elements are described. Among these, the 4,7-diazaindazole compound 2c has improved drug-like properties and kinase selectivity than those of indazole 1, and displays greater than 80% inhibition of GSK3beta phosphorylation in a BT474 tumor xenograft model in mice.
Asunto(s)
Indazoles/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirazinas/química , Piridinas/química , Animales , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Indazoles/síntesis química , Indazoles/farmacología , Ratones , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3beta and tumor growth in a BT474 tumor xenograft model in mice.
Asunto(s)
Aminopiridinas/química , Sistema Enzimático del Citocromo P-450/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirazinas/química , Piridinas/química , Aminopiridinas/síntesis química , Aminopiridinas/farmacocinética , Animales , Línea Celular Tumoral , Perros , Canal de Potasio ERG1 , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Haplorrinos , Humanos , Ratones , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Akt kinases 1, 2, and 3 are important regulators of cell survival and have been shown to be constitutively active in a variety of human tumors. GSK690693 is a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. It causes dose-dependent reductions in the phosphorylation state of multiple proteins downstream of Akt, including GSK3 beta, PRAS40, and Forkhead. GSK690693 inhibited proliferation and induced apoptosis in a subset of tumor cells with potency consistent with intracellular inhibition of Akt kinase activity. In immune-compromised mice implanted with human BT474 breast carcinoma xenografts, a single i.p. administration of GSK690693 inhibited GSK3 beta phosphorylation in a dose- and time-dependent manner. After a single dose of GSK690693, >3 micromol/L drug concentration in BT474 tumor xenografts correlated with a sustained decrease in GSK3 beta phosphorylation. Consistent with the role of Akt in insulin signaling, treatment with GSK690693 resulted in acute and transient increases in blood glucose level. Daily administration of GSK690693 produced significant antitumor activity in mice bearing established human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Immunohistochemical analysis of tumor xenografts after repeat dosing with GSK690693 showed reductions in phosphorylated Akt substrates in vivo. These results support further evaluation of GSK690693 as an anticancer agent.
Asunto(s)
Antineoplásicos/farmacología , Oxadiazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Femenino , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Oxadiazoles/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cell cycle progression is regulated by cyclins and cyclin-dependent kinases, which are formed at specific stages of the cell cycle and regulate the G1/S and G2/M phase transitions, employing a series of "checkpoints" governed by phosphorylation of their substrates. Tumor development is associated with the loss of these checkpoint controls, and this provides an approach for the development of therapeutic agents that can specifically target tumor cells. Here, we describe the synthesis and SAR of a novel group of cytotoxic molecules that selectively induce growth arrest of normal cells in the G1 phase while inducing a mitotic arrest of tumor cells resulting in selective killing of tumor cell populations with little or no effect on normal cell viability. The broad spectrum of antitumor activity in vitro and xenograft models, lack of in vivo toxicity, and drug resistance suggest potential for use of these agents in cancer therapy.
Asunto(s)
Antineoplásicos/síntesis química , Estirenos/síntesis química , Sulfonas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Desnudos , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Estirenos/química , Estirenos/farmacología , Sulfonas/química , Sulfonas/farmacología , Pruebas de ToxicidadRESUMEN
Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. In our quest to develop new BCR-ABL inhibitors, we chose to target regions outside the ATP-binding site of this enzyme because these compounds offer the potential to be unaffected by mutations that make CML cells resistant to imatinib. Here we describe the activity of one compound, ON012380, that can specifically inhibit BCR-ABL and induce cell death of Ph+ CML cells at a concentration of <10 nM. Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.