RESUMEN
Background and Aims: Large clades of angiosperms are often characterized by diverse interactions with pollinators, but how these pollination systems are structured phylogenetically and biogeographically is still uncertain for most families. Apocynaceae is a clade of >5300 species with a worldwide distribution. A database representing >10 % of species in the family was used to explore the diversity of pollinators and evolutionary shifts in pollination systems across major clades and regions. Methods: The database was compiled from published and unpublished reports. Plants were categorized into broad pollination systems and then subdivided to include bimodal systems. These were mapped against the five major divisions of the family, and against the smaller clades. Finally, pollination systems were mapped onto a phylogenetic reconstruction that included those species for which sequence data are available, and transition rates between pollination systems were calculated. Key Results: Most Apocynaceae are insect pollinated with few records of bird pollination. Almost three-quarters of species are pollinated by a single higher taxon (e.g. flies or moths); 7 % have bimodal pollination systems, whilst the remaining approx. 20 % are insect generalists. The less phenotypically specialized flowers of the Rauvolfioids are pollinated by a more restricted set of pollinators than are more complex flowers within the Apocynoids + Periplocoideae + Secamonoideae + Asclepiadoideae (APSA) clade. Certain combinations of bimodal pollination systems are more common than others. Some pollination systems are missing from particular regions, whilst others are over-represented. Conclusions: Within Apocynaceae, interactions with pollinators are highly structured both phylogenetically and biogeographically. Variation in transition rates between pollination systems suggest constraints on their evolution, whereas regional differences point to environmental effects such as filtering of certain pollinators from habitats. This is the most extensive analysis of its type so far attempted and gives important insights into the diversity and evolution of pollination systems in large clades.
Asunto(s)
Apocynaceae/genética , Evolución Biológica , Insectos , Polinización/genética , Animales , Biodiversidad , AvesRESUMEN
A series of taxonomic questions at the subfamilial, generic, and intrageneric levels have remained within subfamily Chlorogaloideae s.s. (comprising Camassia, Chlorogalum, Hastingsia, and Schoenolirion) and relatives in Agavaceae. We present the first phylogenetic hypotheses focused on Chlorogaloideae that are based on multiple independent loci and include a wide sampling of outgroups across Agavaceae. In addition to chloroplast regions ndhF and trnL-trnF, we used nrDNA ITS for phylogenetic inference. Incomplete concerted evolution of the latter is indicated by intra-individual site polymorphisms for nearly half of the individuals. Comparisons of four coding and analysis methods for these characters indicate that the region remains phylogenetically informative. Our results confirm that Chlorogaloideae s.s. is not monophyletic, due to the close relationship of Schoenolirion with Hesperaloe and Hesperoyucca, as well as the likely sister relationship between Hesperocallis and core Chlorogaloideae (Camassia, Chlorogalum, and Hastingsia). Chlorogalum is also not monophyletic, being divided with strong support into vespertine and diurnal clades. This study produced the first phylogenetic hypotheses across Hesperaloe, allowing initial tests of several taxonomic disagreements within this genus. Our results reveal the lack of cohesion of H. funifera, indicating that H. funifera ssp. funifera may be more closely related to H. campanulata than to H. funifera ssp. chiangii (=H. chiangii). With potential gene flow between many members of Hesperaloe and a possible hybrid origin for H. campanulata, the genetic relationships within this genus appear complex. Further population-level investigation of many of the taxa in Chlorogaloideae s.l. would benefit our understanding of the evolution and taxonomy of these groups; Camassia and Hastingsia are the current focus of ongoing study.
Asunto(s)
Asparagaceae/clasificación , Evolución Biológica , Filogenia , Teorema de Bayes , ADN de Cloroplastos/genética , ADN de Plantas/genética , ADN Espaciador Ribosómico/genética , Modelos Genéticos , Análisis de Secuencia de ADNRESUMEN
The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.
Asunto(s)
Bencimidazoles/química , Proteínas Portadoras/agonistas , Proteínas de la Membrana/agonistas , Pirimidinonas/química , Hormonas Tiroideas/agonistas , Sitios de Unión , Proteínas Portadoras/metabolismo , Línea Celular , Diseño Asistido por Computadora , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Cinética , Proteínas de la Membrana/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Pirimidinonas/síntesis química , Pirimidinonas/metabolismo , Relación Estructura-Actividad , Hormonas Tiroideas/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
Despite abundant evidence that aberrant Rho-family GTPase activation contributes to most steps of cancer initiation and progression, there is a dearth of inhibitors of their effectors (e.g., p21-activated kinases). Through high-throughput screening and structure-based design, we identify PF-3758309, a potent (K(d) = 2.7 nM), ATP-competitive, pyrrolopyrazole inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC(50) = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC(50) = 4.7 +/- 3 nM). The molecular underpinnings of PF-3758309 biological effects were characterized using an integration of traditional and emerging technologies. Crystallographic characterization of the PF-3758309/PAK4 complex defined determinants of potency and kinase selectivity. Global high-content cellular analysis confirms that PF-3758309 modulates known PAK4-dependent signaling nodes and identifies unexpected links to additional pathways (e.g., p53). In tumor models, PF-3758309 inhibits PAK4-dependent pathways in proteomic studies and regulates functional activities related to cell proliferation and survival. PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC(50) value of 0.4 nM in the most sensitive model. This study defines PAK4-related pathways, provides additional support for PAK4 as a therapeutic target with a unique combination of functions (apoptotic, cytoskeletal, cell-cycle), and identifies a potent, orally available small-molecule PAK inhibitor with significant promise for the treatment of human cancers.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Modelos Moleculares , Neoplasias/metabolismo , Pirazoles/farmacología , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Quinasas p21 Activadas/antagonistas & inhibidores , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Pirazoles/química , Pirazoles/metabolismo , Pirroles/química , Pirroles/metabolismo , Factores de Intercambio de Guanina Nucleótido RhoRESUMEN
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.
Asunto(s)
Antagonistas de Receptores Androgénicos/síntesis química , Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Indoles/farmacología , Ligandos , Masculino , Modelos Moleculares , Neoplasias de la Próstata , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores Androgénicos/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
(S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity.
Asunto(s)
Aminopiridinas/química , Aminopiridinas/metabolismo , Electrones , Humanos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pruebas de Mutagenicidad , Oxidación-Reducción , Factores de TiempoRESUMEN
High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.
Asunto(s)
Descubrimiento de Drogas , Lactamas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/química , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactamas/síntesis química , Lactamas/química , Masculino , Modelos Moleculares , Estructura Molecular , Neoplasias de la Próstata/cirugía , Receptores Androgénicos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , S-Adenosilmetionina/metabolismo , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Resistencia a Medicamentos , Femenino , Humanos , Neoplasias Pulmonares/patología , RatonesRESUMEN
A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Profármacos/síntesis química , Profármacos/farmacología , Piridonas/síntesis química , Piridonas/farmacología , Animales , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Linfoma de Células B/tratamiento farmacológico , Ratones , Modelos Moleculares , Profármacos/farmacocinética , Piridonas/farmacocinética , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free-Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intravenosas , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/inmunologíaRESUMEN
The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.
Asunto(s)
Diseño de Fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Animales , Línea Celular , Cromatografía Líquida de Alta Presión/métodos , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética/métodos , Ratones , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Ratas , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
Recent human activities have spread numerous plant species across the globe, yet it is unclear to what degree historical human activities influenced plant dispersal. In western North America, Camassia quamash was one of the most important food plants for indigenous peoples, who transported its propagules either intentionally or accidentally. We investigated how human and natural dispersal might have contributed to the current pattern of spatial genetic structure in C. quamash by performing phylogeographical surveys at two geographical scales. We sequenced two noncoding regions of chloroplast deoxyribonucleic acid (DNA) in 226 individuals from 53 populations of C. quamash as well as 126 individuals from 21 populations of the non-food plant Zigadenus venenosus. Contrary to the expectation of anthropogenic transport, C. quamash populations did not exhibit weaker genetic structure than Z. venenosus populations. We also failed to find convincing evidence for signatures of transport. Instead, our data showed strong effects of past glaciation and geographical barriers of the mountains in the Cascade Range, Olympic Peninsula and Vancouver Island. West of the Cascades, the species appears to have largely migrated northward from a southern refugium after deglaciation, whereas few populations having a highly divergent haplotype might have survived in southwestern Washington. Our data suggest that despite substantial ethnobotanical evidence for anthropogenic transport, the current pattern of genetic structure of C. quamash does not show any detectable signatures of transport by indigenous peoples and is better understood as the result of natural dispersal processes.
Asunto(s)
Asparagaceae/genética , Evolución Molecular , Genética de Población , Filogenia , ADN de Cloroplastos/genética , ADN de Plantas/genética , Variación Genética , Geografía , Haplotipos , Humanos , América del Norte , Dinámica Poblacional , Análisis de Secuencia de ADNRESUMEN
A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.
Asunto(s)
Diseño de Fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Isoquinolinas/farmacología , Isoquinolinas/farmacocinética , Administración Oral , Disponibilidad Biológica , Línea Celular Tumoral , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/química , Modelos Moleculares , Conformación MolecularRESUMEN
A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Diseño de Fármacos , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Piridonas/química , Piridonas/farmacología , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ciclización , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Lactamas/química , Lactamas/farmacología , Ratones , Ratones SCID , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Piridonas/uso terapéuticoRESUMEN
First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.
Asunto(s)
Descubrimiento de Drogas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Proteínas Mutantes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Modelos Moleculares , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A new species, Dasineura camassiae Gagné (Diptera: Cecidomyiidae), is described, illustrated and compared to some of its congeners from related hosts and western North America. The new species causes flower galls on Camassia (Agavoideae; Asparagaceae) in the Pacific Northwest. Its current known distribution is Oregon and Washington, USA. Larvae develop in spring in flowers of Camassia spp., causing the young ovaries to enlarge prematurely and eventually abort, without forming seeds or mature fruit. Full-grown larvae crawl out of the gall in rapid succession and drop to the soil where they pupate; they remain there until spring of the following year when the adults emerge and lay eggs. The galls they induce in camas lily buds represent the first known association of the cosmopolitan genus Dasineura with the group of plants that includes Agave and its relatives.
Asunto(s)
Camassia/parasitología , Dípteros/clasificación , Tumores de Planta/parasitología , Distribución Animal , Estructuras Animales/anatomía & histología , Estructuras Animales/crecimiento & desarrollo , Animales , Tamaño Corporal , Dípteros/anatomía & histología , Dípteros/crecimiento & desarrollo , Femenino , Flores/parasitología , Masculino , Noroeste de Estados Unidos , Tamaño de los ÓrganosRESUMEN
PREMISE OF THE STUDY: The North American genus Camassia is an ecologically important group whose variability and evolution are little understood, being influenced by hybridization and geographic isolation. We developed microsatellite markers to investigate patterns of gene flow, population structure, and taxonomic relationships within this group. ⢠METHODS AND RESULTS: Using a traditional approach with biotin-labeled probes, we developed 16 microsatellite primers in three species of Camassia: C. howellii, C. leichtlinii, and C. quamash. The number of alleles per locus averaged 3.94 per species, and levels of heterozygosity ranged from 0.000 to 1.00 and 0.033 to 0.917 for observed and expected heterozygosities, respectively. All primers amplified to varying extents in additional species (C. angusta, C. cusickii, C. scilloides) and in putative species in a related genus (Hastingsia alba, H. atropurpurea, H. bracteosa, H. serpentinicola). ⢠CONCLUSIONS: These microsatellite markers exhibit variation and are useful for ongoing studies of integrative taxonomy and population differentiation within this species complex.
RESUMEN
The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
Asunto(s)
Antineoplásicos/síntesis química , Pirazoles/síntesis química , Pirroles/síntesis química , Quinasas p21 Activadas/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carbamatos/química , Carbamatos/farmacocinética , Carbamatos/farmacología , Cristalografía por Rayos X , Perros , Humanos , Enlace de Hidrógeno , Ratones , Modelos Moleculares , Conformación Molecular , Permeabilidad , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}imidazo[1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.