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 and characterization of clinical candidate PF-06939999.
View Article and Find Full Text PDFThe 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 G kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition.
View Article and Find Full Text PDFControl 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.
View Article and Find Full Text PDFA 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 ) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound ) to animals following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound .
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFBackground 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.
View Article and Find Full Text PDFA 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 sp 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.
View Article and Find Full Text PDFA 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.
View Article and Find Full Text PDFFirst 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.
View Article and Find Full Text PDFA 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.
View Article and Find Full Text PDFA 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.
View Article and Find Full Text PDFPremise 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.
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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFOxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design.
View Article and Find Full Text PDFHigh 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.
View Article and Find Full Text PDFN-{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.
View Article and Find Full Text PDFAn aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
View Article and Find Full Text PDFDespite 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).
View Article and Find Full Text PDFRecent 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.
View Article and Find Full Text PDFNursery pollinators, and the plants they use as hosts for offspring development, function as exemplary models of coevolutionary mutualism. The two pre-eminent examples--fig wasps and yucca moths--show little variation in the interaction: the primary pollinator is an obligate mutualist. By contrast, nursery pollination of certain Caryophyllaceae, including Silene spp.
View Article and Find Full Text PDFReintroductions are increasingly used to enhance declining populations, yet comparative data for critical germination and establishment phases are seldom available for both rare and common herbaceous perennials. After introducing a total of >1800 seeds, we compared experimentally manipulated and natural populations of widespread Silene douglasii var. douglasii relative to rare S.
View Article and Find Full Text PDF