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1.
Mol Cancer Ther ; 22(2): 179-191, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36399631

RESUMEN

The multi-receptor tyrosine kinase inhibitor XL092 has been developed to inhibit the activity of oncogenic targets, including MET, VEGFR2, and the TAM family of kinases TYRO3, AXL and MER. Presented here is a preclinical evaluation of XL092. XL092 causes a significant decrease in tumor MET and AXL phosphorylation (P < 0.01) in murine Hs 746T xenograft models relative to vehicle, and a 96% inhibition of VEGFR2 phosphorylation in murine lungs. Dose-dependent tumor growth inhibition with XL092 was observed in various murine xenograft models, with dose-dependent tumor regression seen in the NCI-H441 model. Tumor growth inhibition was enhanced with the combination of XL092 with anti-PD-1, anti-programmed death ligand-1 (PD-L1), or anti-CTLA-4 compared with any of these agents alone in the MC38 murine syngeneic model and with anti-PD-1 in the CT26 colorectal cancer survival model. In vivo, XL092 promoted a decrease in the tumor microvasculature and significant increases of peripheral CD4+ T cells and B cells and decreases in myeloid cells versus vehicle. Significant increases in CD8+ T cells were also observed with XL092 plus anti-PD-1 or anti-PD-L1 versus vehicle. In addition, XL092 promoted M2 to M1 repolarization of macrophages in vitro and inhibited primary human macrophage efferocytosis in a dose-dependent manner. In summary, XL092 was shown to have significant antitumor and immunomodulatory activity in animal models both alone and in combination with immune checkpoint inhibitors, supporting its evaluation in clinical trials.


Asunto(s)
Neoplasias , Humanos , Animales , Ratones , Proteínas Portadoras , Linfocitos T CD8-positivos , Proteínas Tirosina Quinasas Receptoras , Modelos Animales de Enfermedad , Línea Celular Tumoral
2.
Bioorg Med Chem Lett ; 26(2): 466-471, 2016 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-26687487

RESUMEN

Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.


Asunto(s)
Oxadiazoles/farmacología , Receptores de Lisoesfingolípidos/agonistas , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Células Hep G2 , Humanos , Enlace de Hidrógeno , Cinética , Oxadiazoles/sangre , Oxadiazoles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Tiadiazoles/sangre , Tiadiazoles/síntesis química
3.
Bioorg Med Chem Lett ; 24(20): 4807-11, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25241927

RESUMEN

The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.


Asunto(s)
Oxadiazoles/farmacología , Piperazinas/farmacología , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Linfopenia/inducido químicamente , Linfopenia/patología , Estructura Molecular , Oxadiazoles/administración & dosificación , Oxadiazoles/química , Piperazinas/administración & dosificación , Piperazinas/química , Ratas , Ratas Endogámicas Lew , Receptores de Esfingosina-1-Fosfato , Relación Estructura-Actividad
4.
Bioorg Med Chem Lett ; 22(8): 2693-7, 2012 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-22450127

RESUMEN

Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.


Asunto(s)
Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Animales , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Ratones , Microsomas/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Pirazoles/química , Piridinas/química
5.
Bioorg Med Chem Lett ; 22(6): 2283-6, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22342124

RESUMEN

The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.


Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
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