RESUMEN
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Asunto(s)
Ciclohexanoles/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Proteína Quinasa C-theta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Ciclohexanoles/síntesis química , Ciclohexanoles/metabolismo , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
BACKGROUND: There is often a great urgency to be inclusive when conducting research and to focus efforts with groups and communities that can be referred to as marginalised. This is especially the case in research concerning medical devices aimed at children and young people (CYP). Although involvement methodology has developed over the last two decades, it can be challenging to involve and engage CYP with confidence and clarity of purpose. MAIN BODY: Our aim was to provide a reflective narrative account of the involvement of CYP, over a period of 5 years, in a research project from conception of a new paediatric medical device through to practical application. We explored a model of patient and public involvement (PPI) through the Nottingham Young Persons Advisory Group (YPAG), part of the National Institute for Health Research (NIHR) GenerationR Alliance, in a NIHR funded research project. The YPAG designed and created a model of the human gut, co-designed the Transicap™ mini-capsules and their packaging, co-produced patient information sheets, came up with the idea to disseminate through a project website and co-wrote and created animation videos. The YPAG involvement continued through the writing and award of the follow-on research grant (MAGIC2). During this process the YPAG modified the clinical study protocol insisting that all participants in the control arm were given the imaging test results as well, save for a delayed reading compared to the intervention arm. CONCLUSION: Involvement of the YPAG over the last 5 years, led to the development of a mutually beneficial partnership, enabling genuine knowledge exchange between researchers and CYP. This influenced the design, plans and actions of the MAGIC study and well into the subsequent MAGIC2 follow-on project. Moreover, these involvement models applied within a feasibility study setting, have enhanced the realism and pragmatism of the study, contributing to the project's overall success.
RESUMEN
OBJECTIVE: In England, 27,500 children are referred annually to hospital with constipation. An objective measure of whole gut transit time (WGTT) could aid management. The current standard WGTT assessment, the x-ray radiopaque marker (ROM) test, gives poor definition of colonic anatomy and the radiation dose required is undesirable in children. Our objective was to develop an alternative magnetic resonance imaging (MRI) WGTT measure to the x-ray ROM test and to demonstrate its initial feasibility in paediatric constipation. METHODS: With the Nottingham Young Person's Advisory Group we developed a small (8â×â4âmm), inert polypropylene capsule shell filled with MRI-visible fat emulsion. The capsule can be imaged using MRI fat and water in-phase and out-of-phase imaging. Sixteen patients with constipation and 19 healthy participants aged 7 to 18 years old were recruited. Following a common ROM protocol, the participants swallowed 24 mini-capsules each day for 3 days and were imaged on days 4 and 7 using MRI. The number of successful studies (feasibility) and WGTT were assessed. Participants' EuroQoL Visual Analogue Scale were also collected and compared between the day before the taking the first set of mini-capsules to the day after the last MRI study day. RESULTS: The mini-capsules were imaged successfully in the colon of all participants. The WGTT was 78â±â35âhours (meanâ±âstandard deviation) for patients, and 36â±â16âhours, Pâ<â0.0001 for healthy controls. Carrying out the procedures did not change the EuroQoL Visual Analogue Scale scores before and after the procedures. CONCLUSIONS: Magnetic Resonance Imaging in Paediatric Constipation was a first-in-child feasibility study of a new medical device to measure WGTT in paediatric constipation using MRI. The study showed that the new method is feasible and is well tolerated.
Asunto(s)
Estreñimiento , Tránsito Gastrointestinal , Adolescente , Niño , Colon/diagnóstico por imagen , Estreñimiento/diagnóstico por imagen , Inglaterra , Estudios de Factibilidad , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Mieloma Múltiple/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Ratones , Mieloma Múltiple/patología , Recurrencia , Estereoisomerismo , Insuficiencia del Tratamiento , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/síntesis química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Ratones , Mitosis/efectos de los fármacos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Empalme del ARN/efectos de los fármacos , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/enzimologíaRESUMEN
We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/química , Pirazinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Triazoles/química , Triazoles/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Conformación Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazinas/metabolismo , Pirazinas/farmacocinética , Ratas , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismo , Triazoles/metabolismo , Triazoles/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Pirazinas/síntesis química , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.
Asunto(s)
Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Pirazinas/toxicidad , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Trasplante HeterólogoRESUMEN
The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirimidinas/farmacología , Cristalografía por Rayos X/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Sistema de Señalización de MAP Quinasas , Modelos Químicos , Isoformas de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Urea/químicaRESUMEN
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).