RESUMEN
KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Inmunoterapia , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Fosforilación/efectos de los fármacos , Piperazinas/administración & dosificación , Piperazinas/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/administración & dosificación , Piridinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.
Asunto(s)
Aminas/química , Aminas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Aminas/síntesis química , Carbolinas/síntesis química , Carbolinas/química , Carbolinas/farmacología , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-pim-1/química , Relación Estructura-ActividadRESUMEN
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.
Asunto(s)
Indazoles/química , Indazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Relación Estructura-ActividadRESUMEN
Replacement of the piperazine sulfonamide portion of the PI3Kα inhibitor AMG 511 (1) with a range of aliphatic alcohols led to the identification of a truncated gem-dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol (7). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing.
Asunto(s)
Alcoholes/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Sulfonamidas/química , Triazinas/síntesis química , Animales , Femenino , Semivida , Hígado/metabolismo , Masculino , Ratones , Ratones Desnudos , Conformación Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazina , Piperazinas/metabolismo , Piperazinas/farmacocinética , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/metabolismo , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Triazinas/metabolismo , Triazinas/farmacocinéticaRESUMEN
Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.
Asunto(s)
Nanopartículas , Estereoisomerismo , Estructura Molecular , Preparaciones Farmacéuticas/química , Cristalografía por Rayos X , Nanopartículas/química , Modelos MolecularesRESUMEN
B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.
Asunto(s)
Amidas , N-Acetilglucosaminiltransferasas , Amidas/farmacología , Amidas/química , N-Acetilglucosaminiltransferasas/metabolismo , Diseño de Fármacos , Relación Estructura-ActividadRESUMEN
Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.
Asunto(s)
Benzoatos/química , Benzoatos/síntesis química , Hidrazinas/química , Hidrazinas/síntesis química , Isoindoles/química , Isoindoles/síntesis química , Ftalazinas/química , Ftalazinas/síntesis química , Ftalimidas/química , Pirazoles/química , Pirazoles/síntesis química , Catálisis , Halogenación , Estructura Molecular , EstereoisomerismoRESUMEN
An SAR campaign designed to increase polarity in the 'tail' region of benzothiazole 1 resulted in two series of structurally novel 5-and 6-substituted S1P(1) agonists. Structural optimization for potency ultimately delivered carboxamide (+)-11f, which in addition to possessing improved physicochemical properties relative to starting benzothiazole 1, also displayed good S1P(3) selectivity and acceptable in vivo lymphocyte-depleting activity.
Asunto(s)
Benzotiazoles/química , Linfocitos/efectos de los fármacos , Receptores de Lisoesfingolípidos/agonistas , Receptores de Lisoesfingolípidos/química , Animales , Células CHO , Línea Celular Tumoral , Química Farmacéutica/métodos , Química Física/métodos , Cricetinae , Cricetulus , Diseño de Fármacos , Femenino , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Cetonas , Linfocitos/citología , Modelos Químicos , Ratas , Ratas Endogámicas Lew , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Replacement of the azetidine carboxylate of an S1P(1) agonist development candidate, AMG 369, with a range of acyclic head-groups led to the identification of a novel, S1P(3)-sparing S1P(1) agonist, (-)-2-amino-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-2-methylbutanoic acid (8c), which possessed good in vivo efficacy and pharmacokinetic properties. A 0.3mg/kg oral dose of 8c produced a statistically significant reduction in blood lymphocyte counts 24h post-dosing in female Lewis rats.
Asunto(s)
Aminas/química , Ácidos Carboxílicos/química , Isoformas de Proteínas/química , Piridinas/química , Piridinas/síntesis química , Piridinas/farmacología , Receptores de Lisoesfingolípidos/agonistas , Tiazoles/química , Administración Oral , Animales , Ciclización , Femenino , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica/efectos de los fármacos , Ratas , Ratas Endogámicas Lew , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 µM, 120% efficacy; 5: EC(50)=0.070 µM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 µM; 5: EC(50)=1.5 µM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.
Asunto(s)
Química Física/métodos , Quinolonas/farmacología , Receptores de Lisoesfingolípidos/agonistas , Receptores de Lisoesfingolípidos/química , Animales , Área Bajo la Curva , Enfermedades Cardiovasculares/metabolismo , Diseño de Fármacos , Femenino , Humanos , Inmunosupresores/farmacología , Técnicas In Vitro , Cinética , Linfocitos/citología , Linfocitos/metabolismo , Modelos Químicos , Esclerosis Múltiple/tratamiento farmacológico , Quinolonas/química , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
A comprehensive understanding of structure-reactivity relationships is critical to the design and optimization of cysteine-targeted covalent inhibitors. Herein, we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the α- and ß-positions of the acrylamide moiety. We find that the GSH reaction rates can generally be understood in terms of the electron donating or withdrawing ability of the substituent. When installed at the ß-position, aminomethyl substituents with amine pKa's > 7 accelerate, while those with pKa's < 7 slow the rate of GSH addition at pH 7.4, relative to a hydrogen substituent. Although a computational model was able to only approximately capture experimental reactivity trends, our calculations do not support a frequently invoked mechanism of concerted amine/thiol proton transfer and C-S bond formation and instead suggest that protonated aminomethyl functions as an electron-withdrawing group to reduce the barrier for thiolate addition to the acrylamide.
Asunto(s)
Acrilamidas/síntesis química , Glutatión/química , Acrilamidas/química , Aminas/química , Cisteína/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinonas/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto , Perros , Descubrimiento de Drogas , Humanos , Isomerismo , Células de Riñón Canino Madin Darby , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Piperazinas/química , Piperazinas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Administración Oral , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Disponibilidad Biológica , Cristalografía por Rayos X , Células HeLa , Humanos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/químicaRESUMEN
MDM2 is a key oncogenic protein that serves as a negative regulator of the tumor suppressor p53. While a number of inhibitors of the MDM2-p53 interaction have progressed to clinical testing as treatments for a variety of hematologic and solid tumor cancers, the results thus far have been mixed, with perhaps the strongest responses observed in relapsed/refractory acute myeloid leukemia (AML). In an effort to improve the efficacy for this class of compounds, researchers have turned to targeted degradation of MDM2. IMiD-based MDM2 PROTAC 8, which potently reduces MDM2 protein levels through targeted degradation, exhibits enhanced efficacy in the RS4;11 xenograft model relative to a nondegrading MDM2-p53 inhibitor MI-1061.
Asunto(s)
Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Indoles/química , Indoles/farmacología , Indoles/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Dominios y Motivos de Interacción de Proteínas , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRASG12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRASG12C with submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.
RESUMEN
Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirroles/uso terapéutico , Quinazolinonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Femenino , Humanos , Ratones SCID , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Relación Estructura-Actividad , Porcinos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.
Asunto(s)
Antineoplásicos/síntesis química , Epotilonas/síntesis química , Alcoholes/química , Aniones/química , Ácidos Carboxílicos/síntesis química , Ésteres/química , Indicadores y Reactivos , Lactonas/química , Espectroscopía de Resonancia MagnéticaRESUMEN
Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs. We demonstrate the utility of this approach with the bromodomain and extraterminal domain-4 (BRD4) ligand JQ-1 (3) and ligase binders targeting cereblon (CRBN) and Von Hippel-Lindau (VHL) proteins. An AlphaScreen proximity assay was used to determine the ability of PROTACs to form the ternary ligase-PROTAC-target protein complex and a MSD assay to measure cellular degradation of the target protein promoted by PROTACs.
Asunto(s)
Química Clic , Evaluación Preclínica de Medicamentos , Proteínas Nucleares , Proteolisis , Factores de Transcripción , Humanos , Proteínas Adaptadoras Transductoras de Señales , Proteínas de Ciclo Celular , Química Clic/métodos , Evaluación Preclínica de Medicamentos/métodos , Ligandos , Proteínas Nucleares/metabolismo , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Péptidos/farmacología , Proteolisis/efectos de los fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Benzamidas/síntesis química , Piridinas/síntesis química , Receptor TIE-2/antagonistas & inhibidores , Triazinas/síntesis química , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Sitios de Unión , Proteínas Sanguíneas/metabolismo , Cristalografía por Rayos X , Femenino , Humanos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Fosforilación , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/química , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.