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1.
ACS Med Chem Lett ; 7(4): 351-6, 2016 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-27096040

RESUMEN

Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.

2.
J Med Chem ; 59(3): 985-1002, 2016 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-26741947

RESUMEN

Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kß relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).


Asunto(s)
Antineoplásicos/farmacología , Benzoxepinas/farmacología , Diseño de Fármacos , Imidazoles/farmacología , Oxazepinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzoxepinas/química , Benzoxepinas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/química , Imidazoles/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Macaca fascicularis , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Oxazepinas/química , Oxazepinas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
3.
J Lab Autom ; 21(1): 208-16, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26450876

RESUMEN

Epigenetics continues to emerge as an important target class for drug discovery and cancer research. As programs scale to evaluate many new targets related to epigenetic expression, new tools and techniques are required to enable efficient and reproducible high-throughput epigenetic screening. Assay miniaturization increases screening throughput and reduces operating costs. Echo liquid handlers can transfer compounds, samples, reagents, and beads in submicroliter volumes to high-density assay formats using only acoustic energy-no contact or tips required. This eliminates tip costs and reduces the risk of reagent carryover. In this study, we demonstrate the miniaturization of a methyltransferase assay using Echo liquid handlers and two different assay technologies: AlphaLISA from PerkinElmer and EPIgeneous HTRF from Cisbio.


Asunto(s)
Tecnología Biomédica/métodos , Epigenómica/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Metiltransferasas/análisis , Miniaturización/métodos , Acústica , Soluciones
4.
Bioorg Med Chem Lett ; 23(9): 2606-13, 2013 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-23540645

RESUMEN

A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kß. PI3Kß-sparing compound 27 (PI3Kß Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K ß isoform while maintaining activity against α, δ and γ isoforms is presented.


Asunto(s)
Benzoxepinas/química , Inhibidores Enzimáticos/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Tiazoles/química , Benzoxepinas/síntesis química , Benzoxepinas/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasa/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 23(3): 897-901, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23265894

RESUMEN

Substructural class effects surrounding replacement of a 'cis' N-methyl aniline amide within potent and selective thienobenzoxepin PI3-kinase inhibitors are disclosed. While a simple aryl to alkyl switch was not tolerated due to differences in preferred amide conformation, heterocyclic amide isosteres with maintained aryl substitution improved potency and metabolic stability at the cost of physical properties. These gains in potency allowed lipophilic deconstruction of the arene to simple branched alkyl substituents. As such, overall lipophilicity-neutral, MW decreases were realized relative to the aniline amide series. The improved properties for lead compound 21 resulted in high permeability, solubility and bioavailability.


Asunto(s)
Benzoxepinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Benzotiazoles/química , Benzoxepinas/química , Benzoxepinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Moleculares , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacología
6.
ACS Med Chem Lett ; 4(1): 103-7, 2013 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-24900569

RESUMEN

Aberrant activation of the PI3K-Akt-mTOR signaling pathway has been observed in human tumors and tumor cell lines, indicating that these protein kinases may be attractive therapeutic targets for treating cancer. Optimization of advanced lead 1 culminated in the discovery of clinical development candidate 8h, GDC-0349, a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349 demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models.

7.
J Med Chem ; 55(18): 8007-20, 2012 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-22946614

RESUMEN

Inhibition of phosphoinositide 3-kinase (PI3K) signaling through PI3Kα has received significant attention for its potential in cancer therapy. While the PI3K pathway is a well-established and widely pursued target for the treatment of many cancer types due to the high frequency of abnormal PI3K signaling, glioblastoma multiforme (GBM) is particularly relevant because the pathway is implicated in more than 80% of GBM cases. Herein, we report the identification of PI3K inhibitors designed to cross the blood-brain barrier (BBB) to engage their target where GBM tumors reside. We leveraged our historical experience with PI3K inhibitors to identify correlations between physicochemical properties and transporter efflux as well as metabolic stability to focus the selection of molecules for further study.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Enlace de Hidrógeno , Células de Riñón Canino Madin Darby , Ratones , Permeabilidad , Propiedades de Superficie
8.
J Med Chem ; 55(17): 7686-95, 2012 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-22877085

RESUMEN

Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.


Asunto(s)
Bencimidazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Bencimidazoles/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta
9.
Bioorg Med Chem Lett ; 22(13): 4296-302, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22672799

RESUMEN

A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.


Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Triptófano/química , Animales , Sitios de Unión , Simulación por Computador , Femenino , Inyecciones Intravenosas , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Mutación , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
10.
J Med Chem ; 55(12): 5887-900, 2012 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-22626259

RESUMEN

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, ß, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, ß, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Inhibidores del Citocromo P-450 CYP3A , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Artritis Reumatoide/enzimología , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Línea Celular , Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Conformación Proteica , Especificidad por Sustrato , Factores de Tiempo
11.
J Med Chem ; 54(22): 7815-33, 2011 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-21985639

RESUMEN

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.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Modelos Moleculares , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzoxepinas/química , Benzoxepinas/farmacocinética , Benzoxepinas/farmacología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/química , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Ratones , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacología , Conformación Proteica , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad
12.
J Med Chem ; 54(21): 7579-87, 2011 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-21981714

RESUMEN

The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, ß, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.


Asunto(s)
Antineoplásicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Pirimidinas/síntesis química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Técnicas In Vitro , Isoenzimas/antagonistas & inhibidores , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Conformación Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo
13.
Mol Cancer Ther ; 10(12): 2426-36, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21998291

RESUMEN

Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Neoplasias/tratamiento farmacológico , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Células HCT116 , Humanos , Ratones , Modelos Teóricos , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinasas/clasificación , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/clasificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Bioorg Med Chem Lett ; 20(20): 6048-51, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20822905

RESUMEN

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.


Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/química , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Animales , Línea Celular , Cristalografía por Rayos X , Humanos , Masculino , Ratones , Modelos Moleculares , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias de la Próstata/enzimología , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Ratas , Solubilidad , Relación Estructura-Actividad
16.
Bioorg Med Chem Lett ; 20(8): 2408-11, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20346656

RESUMEN

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.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Tiofenos/farmacología , Animales , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Femenino , Ratones , Pirimidinas/química , Ratas , Serina-Treonina Quinasas TOR , Tiofenos/química
17.
J Med Chem ; 53(3): 1086-97, 2010 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-20050669

RESUMEN

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.


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 , Pirimidinas/farmacología , Tiofenos/farmacología , Administración Oral , Animales , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ib , Isoenzimas/antagonistas & inhibidores , Ratones , Ratones Desnudos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Tiofenos/síntesis química , Tiofenos/química , Ensayos Antitumor por Modelo de Xenoinjerto
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