RESUMEN
The professional autonomy of physicians often requires they take responsibility for life and death decisions, but they must also find ways to avoid bearing the full weight of such decisions. We conducted in-person, semi-structured interviews with neonatologists (n = 20) in four waves between 1978 and 2017 in a single Midwestern U.S. city. Using open coding analysis, we found over time that neonatologists described changes in their sense of professional autonomy and responsibility for decisions with life and death consequences. Through the early 1990s, as neonatology consolidated as a profession, physicians simultaneously enjoyed high levels of professional discretion and responsibility and were often constrained by bioethics and the law. By 2010s, high involvement of parents and collaboration with multiple subspecialties diffused the burden felt by individual practitioners, but neonatology's professional autonomy was correlatively diminished. Decision-making in the NICU over four decades reveal a complex relationship between the professional autonomy of neonatologist and the burden they bear, with some instances of ceding autonomy as a protective measure and other situations of unwelcomed erosion of professional autonomy that neonatologists see as complicating provision of care.
Asunto(s)
Neonatología , Médicos , Toma de Decisiones , Humanos , Neonatólogos , Autonomía Profesional , Investigación CualitativaRESUMEN
Therapeutic development of a targeted agent involves a series of decisions over additional activities that may be ignored, eliminated or pursued. This paper details the concurrent application of two methods that provide a spectrum of information about the biological activity of a compound: biochemical profiling on a large panel of kinase assays and transcriptional profiling of mRNA responses. Our mRNA profiling studies used a full dose range, identifying subsets of transcriptional responses with differing EC(50)s which may reflect distinct targets. Profiling data allowed prioritization for validation in xenograft models, generated testable hypotheses for active compounds, and informed decisions on the general utility of the series.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Quinasa 9 Dependiente de la Ciclina/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor IGF Tipo 1/genética , TriajeRESUMEN
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
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Prolina/química , Inhibidores de Proteínas Quinasas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Triazinas/química , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Triazinas/farmacologíaRESUMEN
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Asunto(s)
Bencimidazoles/química , Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Humanos , Ratones , Ratones Desnudos , Piperazinas/síntesis química , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/síntesis química , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , Inhibidores de Proteínas Quinasas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptores de Esteroides/genética , Activación Transcripcional , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Humanos , Ratones , Ratones Desnudos , Receptor X de Pregnano , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptores de Esteroides/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores del Citocromo P-450 CYP3A , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenosina Trifosfato/química , Administración Oral , Área Bajo la Curva , Química Farmacéutica/métodos , Citocromo P-450 CYP3A/química , Diseño de Fármacos , Flúor/química , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Nitrógeno/química , Receptor IGF Tipo 1/química , Somatomedinas/química , Timidina/químicaRESUMEN
A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Piridonas/química , Piridonas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Unión Proteica , Suero , Relación Estructura-ActividadRESUMEN
The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.
Asunto(s)
Adenocarcinoma/genética , Transformación Celular Neoplásica/genética , Neoplasias Mamarias Experimentales/genética , Receptor IGF Tipo 1/biosíntesis , Neoplasias de las Glándulas Salivales/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antígenos CD8/biosíntesis , Antígenos CD8/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Humanos , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Ratones Transgénicos , Trasplante de Neoplasias , Embarazo , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Neoplasias de las Glándulas Salivales/enzimología , Neoplasias de las Glándulas Salivales/patología , Transfección , Transgenes/genética , Trasplante HeterólogoRESUMEN
Studies of determinants of adoption of new medical technology have failed to coalesce into coherent knowledge. A flaw obscuring strong patterns may be a common habit of treating a wide range of health care innovations as a generic technology. We postulate three decisional systems that apply to different medical technologies with distinctive expertise, interest, and authority: medical-individualistic, fiscal-managerial, and strategic-institutional decisional systems. This review aims to examine the determinants of the adoption of medical technologies based on the corresponding decision-making system. We included quantitative and qualitative studies that analyzed factors facilitating or inhibiting the adoption of medical technologies. In total, 65 studies published between 1974 and 2014 met our inclusion criteria. These studies contained 688 occurrences of variables that were used to examine the adoption decisions, and we subsequently condensed these variables to 62 determinants in four main categories: organizational, individual, environmental, and innovation-related. The determinants and their empirical association with adoption were grouped and analyzed by the three decision-making systems. Although we did not identify substantial differences across the decision-making systems in terms of the direction of the determinants' influence on adoption, a clear pattern emerged in terms of the categories of determinants that were targeted in different decision-making systems.
Asunto(s)
Tecnología Biomédica/normas , Toma de Decisiones en la Organización , Difusión de Innovaciones , Evaluación de la Tecnología Biomédica/normas , Atención a la Salud , Humanos , Innovación Organizacional , Investigación CualitativaRESUMEN
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Piridinas/síntesis química , Piridonas/síntesis química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Piridinas/química , Piridinas/farmacología , Piridonas/química , Piridonas/farmacología , Ratas , Receptor de Insulina/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand-stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition. IRS2 siRNA knockdown reduced IRS2 protein expression levels and decreased sensitivity to BMS-754807, providing evidence for the functional involvement of IRS2 in mediating the drug response. The prevalence of IRS2 CNG in colorectal cancer tumors as measured by qPCR-CNV is approximately 35%. In summary, we identified IRS2 CNG, IGF-1R, IR-A, and IGFBP6 RNA expression levels, and KRAS and BRAF mutational status as candidate predictive biomarkers for response to BMS-754807. This work proposed clinical development opportunities for BMS-754807 in colorectal cancer with patient selection to improve clinical benefit.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/genética , Dosificación de Gen , Proteínas Sustrato del Receptor de Insulina/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Pirazoles/farmacología , Triazinas/farmacología , Proteínas ras/genética , Western Blotting , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Amplificación de Genes/efectos de los fármacos , Humanos , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Ligandos , Modelos Biológicos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras) , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To better understand parental decisions to seek care for their children and physician perceptions of parents' decisions to seek nonurgent emergency-department care. PATIENTS AND METHODS: In-depth interviews of 26 parents of children and 20 primary care physicians of the same children presenting for nonurgent care at a children's hospital emergency department were completed. Parent accounts of events that preceded the emergency-department visit were coded and qualitatively analyzed for themes. Physician evaluations of the accounts of events and parental decisions were ascertained through interviews with primary care physicians, who also described their practice characteristics. The parent/physician analyses allowed for an investigation of all aspects of the child's care and were designed to reveal differences between parent and physician beliefs. RESULTS: Parents believed that they acted appropriately, and physicians approved of parents' decisions. Four main themes emerged: (1) immediate reassurance that their children are safe from harm is critical to parents' decisions; (2) primary care offices lack specific tests and treatments that parents and physicians believe may be necessary, regardless of whether they are actually needed; (3) discrepancies exist between physician and parent perceptions of adequate communication and access; and (4) nonurgent emergency-department visits are not perceived as a significant enough breach in continuity of care by physicians and parents to warrant any concern. CONCLUSIONS: When individual interviews were evaluated, neither parents nor primary care physicians saw nonurgent emergency-department visits as a significant enough problem to warrant any change in physician care practices or parent care-seeking behavior.
Asunto(s)
Servicios Médicos de Urgencia/estadística & datos numéricos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Mal Uso de los Servicios de Salud , Padres , Médicos de Atención Primaria/estadística & datos numéricos , Preescolar , Femenino , Humanos , Lactante , Masculino , Padres/psicología , Relaciones Médico-Paciente , Médicos de Atención Primaria/psicología , Encuestas y CuestionariosRESUMEN
Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Pirazoles/farmacología , Triazinas/farmacología , Animales , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Estradiol/administración & dosificación , Estradiol/análogos & derivados , Estradiol/farmacología , Estrógenos/metabolismo , Femenino , Fulvestrant , Perfilación de la Expresión Génica , Humanos , Letrozol , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nitrilos/administración & dosificación , Nitrilos/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/antagonistas & inhibidores , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Tamoxifeno/administración & dosificación , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Triazoles/administración & dosificación , Triazoles/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Agents targeting insulin-like growth factor-I receptor (IGF-IR), including antibodies and small-molecule inhibitors, are currently in clinical development for the treatment of cancers including sarcoma. However, development of resistance is a common phenomenon resulting in failures of anticancer therapies. In light of this problem, we developed two resistant models from the rhabdomyosarcoma cell line Rh41: Rh41-807R, with acquired resistance to BMS-754807, a small-molecule dual-kinase inhibitor targeting IGF-IR and insulin receptor (IR), and Rh41-MAB391R, with resistance to MAB391, an IGF-IR-blocking antibody. In addition, tumor xenograft models were established from Rh41 and Rh41-807R cell lines. Gene expression and DNA copy number analyses of these models revealed shared as well as unique acquired resistance mechanisms for the two types of IGF-IR inhibitors. Each resistant model used different signaling pathways as a mechanism for proliferation. Platelet-derived growth factor receptor α (PDGFRα) was amplified, overexpressed, and constitutively activated in Rh41-807R cells and tumors. Knockdown of PDGFRα by small interfering RNA in Rh41-807R resensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with PDGFRα inhibitors in the Rh41-807R model in vitro. In contrast, AXL expression was highly elevated in Rh41-MAB391R but downregulated in Rh41-807R. Notably, BMS-754807 was active in Rh41-MAB391R cells and able to overcome resistance to MAB391, but MAB391 was not active in Rh41-807R cells, suggesting potentially broader clinical activity of BMS-754807. This is the first study to define and compare acquired resistance mechanisms for IGF-IR-targeted therapies. It provides insights into the differential acquired resistance mechanisms for IGF-IR/IR small-molecule inhibitor versus anti-IGF-IR antibody.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Pirazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Rabdomiosarcoma/terapia , Triazinas/farmacología , Animales , Anticuerpos Monoclonales/inmunología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Receptor IGF Tipo 1/biosíntesis , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/inmunología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/agonistas , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/deficiencia , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/genética , Rabdomiosarcoma/inmunología , Transfección , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Overexpression and enhanced activity of insulin-like growth factor-I receptor (IGF-IR) in diverse tumor types make it an attractive target for cancer therapy. BMS-536924 is a potent small molecule inhibitor of IGF-IR, which shows antitumor activity in multiple tumor models, including sarcoma. To facilitate the development of IGF-IR inhibitors as cancer therapy, identification of biomarkers for selecting patients most likely to derive clinical benefit is needed. To do so, 28 sarcoma and neuroblastoma cell lines were screened for in vitro response to BMS-536924 to identify sensitive and resistant cell lines. Notably, Ewing's sarcoma, rhabdomyosarcoma, and neuroblastoma are more responsive to BMS-536924, suggesting these specific subtypes may represent potential targeted patient subpopulations for the IGF-IR inhibitor. Gene expression and protein profiling were performed on these cell lines, and candidate biomarkers correlating with intrinsic and/or acquired resistance to BMS-536924 were identified. IGF-I, IGF-II, and IGF-IR were highly expressed in sensitive cell lines, whereas IGFBP-3 and IGFBP-6 were highly expressed in resistant lines. Overexpression of epidermal growth factor receptor (EGFR) and its ligands in resistant cell lines may represent one possible resistance mechanism by the adaptation of IGF-IR-independent growth using alternative signaling pathways. Based on cross-talk between IGF-IR and EGFR pathways, combination studies to target both pathways were performed, and enhanced inhibitory activities were observed. These results provide a strategy for testing combinations of IGF-IR inhibitors with other targeted therapies in clinical studies to achieve improved patient outcomes. Further exploration of mechanisms for intrinsic and acquired drug resistance by these preclinical studies may lead to more rationally designed drugs that target multiple pathways for enhanced antitumor efficacy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencimidazoles/farmacología , Receptores ErbB/antagonistas & inhibidores , Neuroblastoma/tratamiento farmacológico , Piridonas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor IGF Tipo 1/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , Receptor ErbB-2/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/patologíaRESUMEN
BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
Asunto(s)
Pirazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Triazinas/farmacología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Western Blotting , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Triazinas/administración & dosificación , Triazinas/farmacocinética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Asunto(s)
Investigación Biomédica , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Triazinas/farmacología , Animales , Perros , Descubrimiento de Drogas , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Receptor IGF Tipo 1/química , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacocinética , Triazinas/uso terapéuticoRESUMEN
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Bencimidazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Receptor X de Pregnano , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Receptores de Esteroides/efectos de los fármacos , Receptores de Esteroides/metabolismo , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Imidazoles/química , Imidazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Sistema Enzimático del Citocromo P-450/análisis , Imidazoles/síntesis química , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.