RESUMEN
Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.
Asunto(s)
Proteínas Serina-Treonina Quinasas , Transducción de Señal , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Pirroles/farmacologíaRESUMEN
ABSTRACT: Neonatal nurse practitioners (NNPs) are recognized as acute care providers but are actually both acute and primary care providers via education and practice. Neonatal nurse practitioners provide primary care such as anticipatory guidance, care and follow-up of technologically dependent infants, and discharge planning. Numerous interventions and care in the neonatal intensive care unit (NICU) fall under the umbrella of health promotion, an aspect of primary care. In addition, NNPs must also be able to recognize, diagnose, and manage myriad common pediatric illnesses. There is a paucity of data to evaluate how NNP programs are meeting the National Association of Neonatal Nurses educational standards on this topic. A REDCap survey was sent to 31 NNP program directors, with a 100% response rate. All programs provide content addressing primary care management in their curriculum. National recognition of the primary care role, in addition to the acute care role that NNPs practice, should increase opportunities for clinical placement sites, employment opportunities, and grant funding. This article aims to demonstrate both the educational preparation and the delivery of primary care that NNPs provide in the NICU and other areas of practice.
Asunto(s)
Unidades de Cuidado Intensivo Neonatal , Enfermeras Practicantes , Recién Nacido , Humanos , Niño , Enfermeras Practicantes/educación , Curriculum , Atención Primaria de SaludRESUMEN
Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.
Asunto(s)
Antineoplásicos/síntesis química , Encéfalo/metabolismo , Lactamas Macrocíclicas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Aminopiridinas , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Cristalografía por Rayos X , Resistencia a Antineoplásicos , Humanos , Lactamas , Lactamas Macrocíclicas/farmacocinética , Lactamas Macrocíclicas/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Mutación , Células 3T3 NIH , Pirazoles , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).
Asunto(s)
Resistencia a Antineoplásicos/genética , Mutación Puntual , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico , Crizotinib , HumanosRESUMEN
N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/farmacocinética , Sulfonamidas/farmacocinética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacología , Glutatión/farmacocinética , Células HEK293 , Humanos , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide.
Asunto(s)
Antineoplásicos/química , Diseño de Fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Pirimidinonas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Ratones , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridonas/química , Pirimidinas/química , Pirimidinonas/síntesis química , Transducción de Señal , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.
RESUMEN
The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting.
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Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirazinas/farmacología , Triazoles/farmacología , Secuencia de Aminoácidos , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Estabilidad de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Indoles/química , Modelos Moleculares , Datos de Secuencia Molecular , Oxindoles , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Pirazinas/química , Pirazinas/metabolismo , Especificidad por Sustrato , Triazoles/química , Triazoles/metabolismoRESUMEN
Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.
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Antineoplásicos/química , Antineoplásicos/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Pteridinas/química , Pteridinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Humanos , Ratones , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Pteridinas/administración & dosificación , Pteridinas/farmacología , Solubilidad , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The design and development of a series of highly selective pyrrolidine carboxamide 11beta-HSD1 inhibitors are described. These compounds including PF-877423 demonstrated potent in vitro activity against both human and mouse 11beta-HSD1 enzymes. In an in vivo assay, PF-877423 inhibited the conversion of cortisone to cortisol. Structure guided optimization effort yielded potent and stable 11beta-HSD1 selective inhibitor 42.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Amidas/química , Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Pirrolidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/síntesis química , Adamantano/química , Adamantano/farmacología , Amidas/síntesis química , Amidas/farmacología , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cobayas , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Ratones , Microsomas Hepáticos/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Relación Estructura-ActividadRESUMEN
The title compound, C(12)H(19)BrN(4)O, represents the minor component of the two products obtained in a series of transformations involving the Grignard reaction of tert-butoxy-carbonyl-protected 4-amino-cyclo-hexa-none with MeMgBr, and subsequent inter-action of the obtained amino-substituted cyclo-hexa-nol with 4-chloro-6-methyl-pyrimidin-2-amine followed by bromination with N-bromo-succinimide. The X-ray structure showed that this product represents a trans isomer with respect to the amino and hydr-oxy substituents in the cyclo-hexyl ring; the dihedral angle between the amino-pyrimidine plane and the (noncrystallographic) mirror plane of the substituted cyclo-hexyl fragment is 33.6â (3)°. Only two of the four potentially 'active' H atoms participate in inter-molecular N-Hâ¯O and O-Hâ¯N hydrogen bonds, linking the mol-ecules into layers parallel to the (10) plane.