RESUMEN
Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Mutación/genética , Neoplasias/enzimología , Neoplasias/genética , Inhibidores de Proteínas Quinasas/farmacología , Quinasas raf/genética , Proteínas ras/genética , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Concentración 50 Inhibidora , Ratones Desnudos , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/química , Pirimidinas/farmacología , Quinazolinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors but shows very limited expression in normal adult tissues. ASN004 is a 5T4-targeted antibody-drug conjugate (ADC) that incorporates a novel single-chain Fv-Fc antibody and Dolaflexin drug-linker technology, with an Auristatin F hydroxypropylamide payload drug-to-antibody ratio of approximately 10-12. The pharmacology, toxicology, and pharmacokinetic properties of ASN004 and its components were investigated in vitro and in vivo ASN004 showed high affinity for the 5T4 antigen and was selectively bound to and internalized into 5T4-expressing tumor cells, and potent cytotoxicity was demonstrated for a diverse panel of solid tumor cell lines. ASN004 induced complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a wide range of 5T4 expression levels. A single dose of ASN004, as low as 1 mg/kg i.v., achieved complete tumor regression leading to tumor-free survivors in the A431 cervical cancer model. In head-to-head studies, superior activity of ASN004 was demonstrated against trastuzumab-DM1, in a low-5T4/high-HER2 expressing gastric tumor model, and 10-fold greater potency was found for ASN004 against the 5T4-targeted ADC PF-06263507 in a lung tumor model. In marmoset monkeys, ASN004 was well tolerated at doses up to 1.5 mg/kg Q3W i.v., and showed dose-dependent exposure, linear pharmacokinetics, and markedly low exposure of free payload drug. Taken together, these findings identify ASN004 as a promising new ADC therapeutic for clinical evaluation in a broad range of solid tumor types.
Asunto(s)
Anticuerpos Monoclonales Humanizados/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inmunoconjugados/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Glicoproteínas de Membrana/antagonistas & inhibidores , Anticuerpos de Cadena Única/química , Animales , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Ratones SCID , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The interaction of spin and intrinsic orbital angular momentum of light is observed, as evidenced by length-dependent rotations of both spatial patterns and optical polarization in a cylindrically symmetric isotropic optical fiber. Such rotations occur in a straight few-mode fiber when superpositions of two modes with parallel and antiparallel orientation of spin and intrinsic orbital angular momentum (IOAM=2â) are excited, resulting from a degeneracy splitting of the propagation constants of the modes.
RESUMEN
We present an experimental method for creating and verifying photon-number states created by non-degenerate, third-order nonlinear-optical photon-pair sources. By using spatially multiplexed, thresholding single-photon detectors and inverting a conditional probability matrix, we determine the photon-number probabilities created through heralded spontaneous four-wave-mixing. The deleterious effects of noise photons on reliable heralding are investigated and shown to degrade the conditional preparation of two-photon number states more than they degrade conditional single-photon states. We derive the equivalence between the presence of unwanted noise in the herald channel and loss in the signal channel of heralded experiments. A procedure for characterizing the noise-photon contributions, and a means of estimating the herald noise-free photon-number distribution is demonstrated.
RESUMEN
BACKGROUND: Radical rectal resection with total mesorectal excision is the current standard of care for the operative treatment of rectal cancer. Local excision is an acceptable alternative in selected patients with early disease (T(is)0-T(1)) and low-risk features, in whom radical resection may be associated with unacceptably high morbidity. With recent data demonstrating favorable results in well-selected patients, the role of local excision for rectal cancer is expanding.1 (,) 2 Transanal endoscopic microsurgery (TEM), which requires the use of an operating anoscope, has been used for the local excision of mid-upper rectal tumors. We describe an alternative approach to TEM for rectal cancer. METHODS: We present a stepwise technique for TEM using a single-incision laparoscopic (SILS) port. The patient is a 64 year-old male with a right anterolateral rectal polyp 7 cm from the anal verge, which on snare polypectomy demonstrated in-situ carcinoma with positive margins. Endoscopic ultrasound demonstrated uT(1) disease with no lymphadenopathy. He opted for local excision and underwent TEM. Our stepwise approach includes: (1) delineation of excision margins, (2) full thickness incision of the rectal wall, (3) circumferential dissection, and full thickness excision, and (4) suture repair. RESULTS: The procedure was performed without intraoperative or postoperative complications. Final pathology revealed in-situ carcinoma with widely negative margins. At 1- and 3-week follow-up visits, the patient was pain free with normal bowel activity and no rectal bleeding or genitourinary dysfunction. DISCUSSION: TEM using a SILS port is an effective technique for the local excision of mid-upper rectal cancer in well-selected patients.
Asunto(s)
Carcinoma in Situ/cirugía , Laparoscopía/métodos , Microcirugia/métodos , Neoplasias del Recto/cirugía , Canal Anal/cirugía , Endoscopía , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K(i)=3.7nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.
Asunto(s)
Fármacos Antiobesidad/farmacología , Peso Corporal/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/uso terapéutico , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Imidazoles/uso terapéutico , Obesidad/tratamiento farmacológico , Ratas , Ratas Zucker , Receptores de Cannabinoides/metabolismo , Relación Estructura-ActividadRESUMEN
A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Piridonas/síntesis química , Pirroles/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/farmacocinética , Peso Corporal/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Obesidad/tratamiento farmacológico , Piridonas/farmacocinética , Piridonas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Wistar , Ratas Zucker , Rimonabant , Relación Estructura-Actividad , Aumento de Peso/efectos de los fármacosRESUMEN
Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) - from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 - was completed in just 11 years, with approval being received approximately 5 years after the initiation of the first Phase I trial.
Asunto(s)
Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , Bencenosulfonatos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Ensayos Clínicos como Asunto , Técnicas Químicas Combinatorias , Humanos , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/farmacología , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sorafenib , Quinasas raf/antagonistas & inhibidoresRESUMEN
The RAS-RAF-MEK-ERK signaling pathway (ERK pathway) plays a key role in tumorigenesis and cancer progression. Mutations of RAS or B-RAF lead to a constitutive activation of the ERK pathway, which ultimately results in increased cell division, and cell survival. This review article focuses on the recent literature related to ERK pathway inhibitors, with a particular emphasis on RAF kinase inhibitors. Preclinical and clinical data for the RAF kinase inhibitor sorafenib (BAY 43-9006 tosylate), that was recently approved in the US for the treatment of advanced renal cell carcinoma, are also outlined.
Asunto(s)
Antineoplásicos , Inhibidores Enzimáticos , Neoplasias/tratamiento farmacológico , Quinasas raf/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Estructura Molecular , Neoplasias/enzimologíaRESUMEN
The worldwide prevalence of obesity has dramatically increased over the last 30 years, yet due to modest efficacy and side effects, current treatments for obesity are inadequate. Antagonists of the cannabinoid receptor type 1 (CB(1)) have emerged as a highly promising therapeutic strategy for obesity, with the 1,5-diaryl-pyrazole rimonabant (Sanofi-Aventis) being the most characterized and the furthest advanced agent in the clinic. This review focuses on recent publications (2002 to 2004) that describe the effects of CB(1) antagonists both on feeding behavior and in models of obesity, and the identification and characterization of new structure classes as CB(1) antagonists.
Asunto(s)
Obesidad/tratamiento farmacológico , Receptor Cannabinoide CB1/antagonistas & inhibidores , Tecnología Farmacéutica/métodos , Animales , Cannabinoides/antagonistas & inhibidores , Cannabinoides/metabolismo , Humanos , Obesidad/metabolismo , Receptor Cannabinoide CB1/metabolismo , Tecnología Farmacéutica/tendenciasRESUMEN
With two compounds on the market (Gleevec and Iressa), and a number of drug candidates in late-stage clinical trials, small-molecule kinase inhibitors hold great potential as novel therapies for cancer and inflammatory disorders. Inhibitors from the urea class were first reported in 1996 and have emerged as an important compound class for medicinal chemists due to their unique binding mode and kinase inhibition profile. Currently, five members of this class are undergoing clinical trials, BIRB-796 (Boehringer Ingelheim Pharmaceuticals Inc), BAY-43-9006 (Bayer AG/Onyx Pharmaceuticals Inc), CP-547632 (Pfizer Inc), MLN-518 (Millennium Pharmaceuticals Inc) and KRN-951 (Kirin Brewery Co Ltd). This review focuses on the most recent developments in the discovery of urea-based protein kinase inhibitors.
Asunto(s)
Química Farmacéutica/métodos , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Urea/análogos & derivados , Química Farmacéutica/tendencias , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Humanos , Estructura Molecular , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Urea/química , Urea/uso terapéuticoRESUMEN
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Quinasa 1 de Quinasa de Quinasa MAP , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Urea/análogos & derivados , Urea/farmacología , Amidas/síntesis química , Amidas/farmacología , Baculoviridae/genética , Inhibidores Enzimáticos/síntesis química , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Solubilidad , Relación Estructura-Actividad , Urea/síntesis químicaRESUMEN
Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.
Asunto(s)
Compuestos de Bencilo/química , Compuestos de Bencilo/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de Glucagón/antagonistas & inhibidores , Concentración 50 Inhibidora , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Animales , División Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Relación Estructura-ActividadRESUMEN
A library of benzofurans was prepared by solid-phase synthesis methods, and several analogues were identified as potent ligands for the estrogen receptors ER-alpha and ER-beta, with some compounds having selectivity for ER-alpha. Analogues designed to more closely mimic Raloxifene were less effective. Certain benzofurans were effective in a bone pit assay, but were characterized as agonists in a MCF-7 breast tumor cell proliferation assay.
Asunto(s)
Benzofuranos/síntesis química , Benzofuranos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular , Diseño de Fármacos , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Femenino , Humanos , Modelos Moleculares , Clorhidrato de Raloxifeno/farmacología , Receptores de Estrógenos/efectos de los fármacosRESUMEN
Inhibitors of the MAP kinase p38 provide a novel approach for the treatment of osteoporosis, inflammatory disorders, and cancer. We have identified N-(3-tert-butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea as a potent and selective p38 kinase inhibitor in biochemical and cellular assays. This compound is orally active in two acute models of cytokine release (TNF-induced IL-6 and LPS-induced TNF) and a chronic model of arthritis (20-day murine collagen-induced arthritis).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Urea/síntesis química , Urea/farmacología , Administración Oral , Animales , Artritis/tratamiento farmacológico , Citocinas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Ratones , Urea/análogos & derivados , Urea/química , Urea/uso terapéutico , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.