RESUMEN
We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triazinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/química , Triazinas/metabolismoRESUMEN
PURPOSE: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. EXPERIMENTAL DESIGN: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. RESULTS: In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (â¼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). CONCLUSION: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.
Asunto(s)
Morfolinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triazinas/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Femenino , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Morfolinas/farmacología , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Triazinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Analogues of the sponge meroterpenoid liphagal have been synthesized and evaluated for inhibition of PI3Kα and PI3Kγ as part of a program aimed at developing new isoform-selective PI3K inhibitors. One of the analogues, compound 24, with IC50 values of 66 nM against PI3Kα and 1840 nM against PI3Kγ, representing a 27-fold preference for PI3Kα, exhibited enhanced chemical stability and modestly enhanced potency and selectivity compared with the natural product liphagal.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Poríferos , Terpenos/síntesis química , Animales , Estabilidad de Medicamentos , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Fosfatidilinositol 3-Quinasa/química , Estereoisomerismo , Relación Estructura-Actividad , Terpenos/químicaRESUMEN
A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.
Asunto(s)
Morfolinas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triazinas/química , Urea/análogos & derivados , Administración Oral , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos , Morfolinas/síntesis química , Morfolinas/farmacocinética , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismo , Triazinas/síntesis química , Triazinas/farmacocinética , Tropanos/química , Urea/síntesis química , Urea/química , Urea/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Benzofuranos/química , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Ratones , Ratones Desnudos , Microsomas , Ratas , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Carga Tumoral/efectos de los fármacos , Urea/uso terapéuticoRESUMEN
PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR; IC(50) versus PI3K-alpha = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non-small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm(3) to 129 mm(3) and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Compuestos de Fenilurea/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Biomarcadores de Tumor/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Pruebas de Enzimas , Factores de Transcripción Forkhead/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Concentración 50 Inhibidora , Ratones , Compuestos de Fenilurea/sangre , Compuestos de Fenilurea/química , Poli(ADP-Ribosa) Polimerasas/metabolismo , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/sangre , Pirimidinas/química , Serina-Treonina Quinasas TORRESUMEN
Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110alpha isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kalpha and mTOR, leading to the discovery of PI3Kalpha selective inhibitors (e.g., 9) and dual PI3Kalpha/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kalpha/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.
Asunto(s)
Benzamidas/síntesis química , Morfolinas/síntesis química , Compuestos de Fenilurea/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirimidinas/síntesis química , Pirroles/síntesis química , Animales , Benzamidas/química , Benzamidas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Ratones , Ratones Desnudos , Modelos Moleculares , Morfolinas/química , Morfolinas/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Fosforilación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Trasplante HeterólogoRESUMEN
A series of 5-ureidobenzofuranones was discovered as potent and selective inhibitors of mTOR with good cellular activity. Molecular modeling studies revealed several hydrogen bond interactions of the ureido group with the enzyme at the ATP-binding site. Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented.
Asunto(s)
Adenosina Trifosfato/metabolismo , Benzofuranos/química , Benzofuranos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Fosfatidilinositol 3-Quinasa Clase Ib , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Péptidos y Proteínas de Señalización Intracelular/química , Isoenzimas/química , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Sirolimus , Homología Estructural de Proteína , Serina-Treonina Quinasas TORRESUMEN
We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Microsomas/metabolismo , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhibitors. Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration.
Asunto(s)
Adenosina Trifosfato/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Morfolinas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazinas/química , Triazinas/farmacología , Animales , Descubrimiento de Drogas , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Serina-Treonina Quinasas TORRESUMEN
A series of benzofuran-3-one indole phosphatidylinositol-3-kinases (PI3K) inhibitors identified via HTS has been prepared. The optimized inhibitors possess single digit nanomolar activity against p110alpha (PI3K-alpha), good pharmaceutical properties, selectivity versus p110gamma (PI3K-gamma), and tunable selectivity versus the mammalian target of rapamycin (mTOR). Modeling of compounds 9 and 32 in homology models of PI3K-alpha and mTOR supports the proposed rationale for selectivity. Compounds show activity in multiple cellular proliferation assays with signaling through the PI3K pathway confirmed via phospho-Akt inhibition in PC-3 cells.
Asunto(s)
Benzofuranos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Benzofuranos/química , Línea Celular Tumoral , Humanos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazinas/farmacología , Adenosina Trifosfato/química , Adenosina Trifosfato/farmacología , Animales , Área Bajo la Curva , Unión Competitiva , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Desnudos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Morfolinas/química , Morfolinas/farmacocinética , Morfolinas/farmacología , Mutación , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/prevención & control , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Análisis de Supervivencia , Serina-Treonina Quinasas TOR , Triazinas/química , Triazinas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.
Asunto(s)
Adenosina Trifosfato/metabolismo , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química , Pirazoles/química , Piridinas/química , Adenosina Trifosfato/química , Administración Oral , Animales , Unión Competitiva , Estabilidad de Medicamentos , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Microsomas/enzimología , Estructura Molecular , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/síntesis química , Piridinas/síntesis química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/química , Pirazoles/química , Piridinas/química , Sitios de Unión , Células CACO-2 , Línea Celular Tumoral , Cristalografía por Rayos X , Inmunoensayo de Polarización Fluorescente , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Purinas/síntesis química , Purinas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
The morpholine hinge-region binding group on a series of pyrazolopyrimidine and thienopyrimidine mammalian target of rapamycin (mTOR) inhibitors was replaced with 3,6-dihydro-2H-pyran (DHP), giving compounds of equivalent potency and selectivity versus PI3K. These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Morfolinas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piranos/química , Pirazoles/química , Piridinas/química , Pirimidinas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión , Unión Competitiva , Simulación por Computador , Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Microsomas/metabolismo , Modelos Moleculares , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Serina-Treonina Quinasas TORRESUMEN
2-Aryl-4-morpholinothieno[3,2-d]pyrimidines are known PI3K inhibitors. This class of compounds also potently inhibited the homologous enzyme mTOR. Replacement of the morpholine group in these compounds with an 8-oxa-3-azabicyclo[3.2.1]octane group led to mTOR inhibitors with selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-(4-ureidophenyl)-thienopyrimidines as highly potent (IC(50) <1nM) mTOR inhibitors with excellent selectivity (up to >1000-fold) over PI3K and good potency in a cellular proliferation assay (IC(50) <50nM).
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Tropanos/química , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Morfolinas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Sitios de Unión , Unión Competitiva , Línea Celular Tumoral , Simulación por Computador , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Serina-Treonina Quinasas TORRESUMEN
Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Triazoles/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ib , Humanos , Isoenzimas/antagonistas & inhibidores , Pirimidinas/farmacología , Ratas , Serina-Treonina Quinasas TOR , Triazoles/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase alpha (PI3K-alpha), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC(50) against mTOR and greater than 1000-fold selectivity over PI3K-alpha. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC(50) < 1 nM) with unprecedented activity in cellular proliferation assays (IC(50) < 1 nM).
Asunto(s)
Adenosina Trifosfato/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Pirimidinas/farmacología , Adenosina Trifosfato/metabolismo , Unión Competitiva , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Masculino , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/química , Morfolinas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
A series of highly potent and selective pyrazolopyrimidine mTOR inhibitors which contain water-solubilizing groups attached to the 6-arylureidophenyl moiety have been prepared. Such derivatives displayed superior potency to those in which these appendages were attached to alternative sites. In comparison to unfunctionalized arylureido compounds, these analogs demonstrated enhanced cellular potency and significantly improved stability towards human microsomes, resulting in an mTOR inhibitor with impressive efficacy in a xenograft model with an intermittent dosing regimen.