RESUMEN
Structure-guided design led to the discovery of novel chemical scaffolds for B-Raf inhibitors. Both type I and type II kinase inhibitors have been explored and lead compounds with good potency and excellent selectivity have been identified.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Isoindoles/síntesis química , Ftalazinas/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Bencenosulfonatos/química , Bencenosulfonatos/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Imidazoles/química , Imidazoles/farmacología , Isoindoles/química , Isoindoles/farmacología , Modelos Moleculares , Estructura Molecular , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Ftalazinas/química , Ftalazinas/farmacología , Piridinas/química , Piridinas/farmacología , Sorafenib , Relación Estructura-ActividadRESUMEN
A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/farmacología , Pirimidinas/farmacología , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The serine/threonine kinase AKT/PKB plays a critical role in cancer and represents a rational target for therapy. Although efforts in targeting AKT pathway have accelerated in recent years, relatively few small molecule inhibitors of AKT have been reported. The development of selective AKT inhibitors is further challenged by the extensive conservation of the ATP-binding sites of the AGC kinase family. In this report, we have conducted a high-throughput screen for inhibitors of activated AKT1. We have identified lactoquinomycin as a potent inhibitor of AKT kinases (AKT1 IC(50), 0.149 +/- 0.045 micromol/L). Biochemical studies implicated a novel irreversible interaction of the inhibitor and AKT involving a critical cysteine residue(s). To examine the role of conserved cysteines in the activation loop (T-loop), we studied mutant AKT1 harboring C296A, C310A, and C296A/C310A. Whereas the ATP-pocket inhibitor, staurosporine, indiscriminately targeted the wild-type and all three mutant-enzymes, the inhibition by lactoquinomycin was drastically diminished in the single mutants C296A and C310A, and completely abolished in the double mutant C296A/C310A. These data strongly implicate the binding of lactoquinomycin to the T-loop cysteines as critical for abrogation of catalysis, and define an unprecedented mechanism of AKT inhibition by a small molecule. Lactoquinomycin inhibited cellular AKT substrate phosphorylation induced by growth factor, loss of PTEN, and myristoylated AKT. The inhibition was substantially attenuated by coexpression of C296A/C310A. Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors.
Asunto(s)
Cisteína/metabolismo , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Adenosina Trifosfato/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Catálisis/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Cinética , Naftoquinonas/química , Naftoquinonas/farmacología , Fosforilación/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Quinasas/metabolismo , Caperuzas de ARN/metabolismo , Ratas , Relación Estructura-Actividad , Especificidad por Sustrato/efectos de los fármacos , Serina-Treonina Quinasas TOR , Factores de TiempoRESUMEN
Specific mutations in the ras gene impair the guanosine triphophatase (GTPase) activity of Ras proteins, which play a fundamental role in the signaling cascade, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor onto cell membranes and cannot induce this transformation. Posttranslational modification and plasma membrane association of mutant Ras is necessary for this transforming activity. Since its identification, the enzyme protein farnesyltransferase (FTase) that catalyzes the first and essential step of the three Ras-processing steps has emerged as the most promising target for therapeutic intervention. FTase has been implicated as a potential target in inhibiting the prenylation of a variety of proteins, thus in controlling varied disease states (e.g. cancer, neurofibromatosis, restenosis, viral hepatitis, bone resorption, parasitic infections, corneal inflammations, and diabetes) associated with prenyl modifications of Ras and other proteins. Furthermore, it has been suggested that FTase inhibitors indirectly help in inhibiting tumors via suppression of angiogenesis and induction of apoptosis. Major milestones have been achieved with small-molecule FTase inhibitors that show efficacy without toxicity in vitro, as well as in mouse models bearing ras-dependent tumors. With the determination of the crystal structure of mammalian FTase, existent leads have been fine-tuned and new potent molecules of diverse structural classes have been designed. A few of these molecules are currently in the clinic, with at least three drug candidates in Phase II studies and one in Phase III. This article will review the progress that has been reported with FTase inhibitors in drug discovery and in the clinic.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Inductores de la Angiogénesis , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Membrana Celular/metabolismo , Ensayos Clínicos como Asunto , Cisteína/análogos & derivados , Cisteína/metabolismo , Inhibidores Enzimáticos/química , Farnesiltransferasa , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fosfatos de Poliisoprenilo/química , Fosfatos de Poliisoprenilo/metabolismo , Prenilación de Proteína/efectos de los fármacos , Procesamiento Proteico-Postraduccional , Sesquiterpenos , Proteínas ras/química , Proteínas ras/metabolismoRESUMEN
Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Indazoles/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indazoles/química , Indazoles/farmacología , Ratones , Modelos Moleculares , Mutación , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas B-raf/genética , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.
Asunto(s)
Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/síntesis química , Enlace de Hidrógeno , Estructura Molecular , Solventes/química , EstereoisomerismoRESUMEN
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.