Search

Introduction Knowledge mobilization, specifically dissemination, and research partnerships are helpful for ensuring research is translated to practice. However, empirical data reporting on the processes and outcomes of a partnership approach to dissemination are limited. Sharing and promoting the Integrated Knowledge Translation (IKT) Guiding Principles for conducting and disseminating spinal cord injury research in partnership provide an ideal opportunity to demonstrate the processes and outcomes of a partnership approach to dissemination. Methods The dissemination process of the IKT Guiding Principles included four iterative phases: 1) planning dissemination, 2) conducting dissemination; 3) evaluating dissemination, and 4) reflecting on dissemination. Dissemination activities and outcomes were tracked using 5 sources: a partnership tracking survey, a partnership curriculum vitae, Google Analytics, team emails, and a citation-forward search. Important outcomes tracked were exposure, engagement, and citations. Exposure and engagement to the IKT Guiding Principles were defined as the number of times and/or locations the IKT Guiding Principles were accessed and/or downloaded. Results The IKT Guiding Principles Partnership planned dissemination of the guiding principles from the beginning of the project. Dissemination activities formally commenced with a variety of approaches including direct emails, social media posts, a webinar, academic and community presentations, journal publications. Within the first 20 months of publication, the guiding principles were viewed 3058 times, accessed in 31 different countries (exposure), downloaded 282 times (engagement), and cited 30 times. Conclusion This project provides an overview of metrics and methodology that can be used to monitor and evaluate the processes and outcomes of an IKT approach to dissemination. Overall, a co-production approach may be helpful for disseminating research findings; however, more research is needed to understand the impact of an IKT approach on the dissemination and implementation of research findings.

Target-engagement pharmacodynamic (PD) biomarkers are valuable tools in the prioritization of drug candidates, especially for novel, first-in-class mechanisms whose robustness to alter disease outcome is unknown. Methionine aminopeptidase 2 (MetAP2) is a cytosolic metalloenzyme that cleaves the N-terminal methionine from nascent proteins. Inhibition of MetAP2 leads to weight loss in obese rodents, dogs and humans. However, there is a need to develop efficacious compounds that specifically inhibit MetAP2 with an improved safety profile. The objective of this study was to identify a PD biomarker for selecting potent, efficacious compounds and for predicting clinical efficacy that would result from inhibition of MetAP2. Here we report the use of NMet14-3-3γ for this purpose. Treatment of primary human cells with MetAP2 inhibitors resulted in an approx. 10-fold increase in NMet14-3-3γ levels. Furthermore, treatment of diet-induced obese mice with these compounds reduced body weight (approx. 20%) and increased NMet14-3-3γ (approx. 15-fold) in adipose tissues. The effects on target engagement and body weight increased over time and were dependent on dose and administration frequency of compound. The relationship between compound concentration in plasma, NMet14-3-3γ in tissue, and reduction of body weight in obese mice was used to generate a pharmacokinetic-pharmacodynamic-efficacy model for predicting efficacy of MetAP2 inhibitors in mice. We also developed a model for predicting weight loss in humans using a target engagement PD assay that measures inhibitor-bound MetAP2 in blood. In summary, MetAP2 target engagement biomarkers can be used to select efficacious compounds and predict weight loss in humans. SIGNIFICANCE STATEMENT: The application of target engagement pharmacodynamic biomarkers during drug development provides a means to determine the dose required to fully engage the intended target and an approach to connect the drug target to physiological effects. This work exemplifies the process of using target engagement biomarkers during preclinical research to select new drug candidates and predict clinical efficacy. We determine concentration of MetAP2 antiobesity compounds needed to produce pharmacological activity in primary human cells and in target tissues from an appropriate animal model and establish key relationships between pharmacokinetics, pharmacodynamics, and efficacy, including the duration of effects after drug administration. The biomarkers described here can aid decision-making in early clinical trials of MetAP2 inhibitors for the treatment of obesity.

Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC

Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with

Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd 5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values

A series of arylaminobenzimidazoles was designed and synthesized as Raf kinase inhibitors. Exploration of the structure-activity relationship resulted in compounds that are potent in vitro and show desirable in vivo properties.

The 3-benzimidazol-2-yl-1H-indazole scaffold was developed as an alternate scaffold for our receptor tyrosine kinase (RTK) inhibitor program. In exploring the SAR of this series, it was discovered that a subset of these compounds potently inhibit the enzyme c-ABL. The SAR of these compounds is described.

We herein describe the discovery of a mild, one-pot tandem acylation–cyclization for the synthesis of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones from 2-aminobenzenecarbonitriles and ethyl 2-benzimidazol-2-yl acetates.

Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.

[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.

Benzimidazole reverse amides were designed and synthesized as Pan RAF kinase inhibitors. Investigation of the structure–activity relationship of the compounds revealed that they were potent in vitro and exhibited desirable in vivo properties.

Potassium permanganate absorbed on alumina is used to oxidize 1,4-cyclohexadienes to the corresponding aromatic compounds. Intermolecular Diels-Alder reactions followed by dehydrogenation of the products with potassium permanganate supported on alumina gives an efficient two step synthesis of highly substituted aromatic compounds from acyclic precursors.

The word worship, which in Late Middle English named an obligation-related social value, had by early modem times been largely replaced with honour. This article uses collocational data from two literary texts - Malory's Works and Spenser's The Faerie Queene - to propose an explanation for this change. Patterns of lexical connection for worship and honour support their respective assignment to two different social paradigms, status and contract. The different semantic categories which are present in the collocational data suggest that the change from worship to honour may be part of a larger rearrangement of the vocabulary of obligation in the period, caused by the contemporary shift of dominant social paradigm from status to contract. A sociohistorical analogue to the linguistic case is also presented.

Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. As high expression of PIM1, 2, and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts toward this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000-fold to yield compounds with pan PIM Kis < 10 pM, nanomolar cellular potency, and in vivo activity in an acute myeloid leukemia Pim-dependent tumor model is described.

A ligand-based 3D pharmacophore model for serine/threonine kinase CDC7 inhibition was created and successfully applied in the discovery of novel 2-(heteroaryl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-ones. The pharmacophore model provided a hypothesis for lead generation missed by docking to a homology model. Medicinal chemistry exploration of the series revealed clear structure–activity relationships consistent with the pharmacophore model and pointed to further optimization opportunities.

Potassium permanganate absorbed on alumina is used to oxidize 1,4-cyclohexadienes to the corresponding aromatic compounds. Intermolecular Diels-Alder reactions followed by dehydrogenation of the products with potassium permanganate supported on alumina gives an efficient two step synthesis of highly substituted aromatic compounds from acyclic precursors.

This chapter examines travel writing by Americans during the nineteenth and early twentieth centuries that focuses on extra-continental journeys to islands. Although America was initially “discovered” by sea, the settlement of the United States by immigrants focused largely on filling the empty spaces on the continental map. However, by the mid-nineteenth century, the Western frontier was rapidly vanishing as the transcontinental railroad, telegraph service, and steamships emerged. Needing more land, the nation looked abroad, turning its attention towards the islands of the South Pacific, Cuba, and Hawaii. As the land frontier closed, the sea voyage became important for both imperial and literary exploration. The travel writing that results enables us to understand the relationship between American colonial and literary activity abroad. To begin the study of American travel to the South Pacific, we must acknowledge the place the Marquesas Islands hold in the history of American imperialism. In 1815, American naval captain David Porter proposed to President James Madison that he be allowed to lead an American exploration voyage to the Pacific in order to explore potential commercial development and pursue military colonization. After his arrival at Nukuheva, Porter notified President Madison and Secretary of State James Monroe that he had annexed the Marquesas in the name of the United States. Though neither acknowledged Porter's letters, Porter's claim established these islands in the American imagination as a possible site for overseas expansion and trade. As a result, subsequent writers adopted this model of conquest in their attitudes towards foreign cultures.

3-Benzimidazol-2-yl-1H-indazole analogs were developed as inhibitors of receptor tyrosine kinases (RTK). The synthesis and SAR of this series is reported.

Herein are described a series of novel heterocyclic analogs of the 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one scaffold. These compounds are potent inhibitors of receptor tyrosine kinases and exhibit favorable pharmacokinetic profiles. The synthesis and SAR of these compounds are described.

The error is on page 990 in Table 1. Compound 11 should be 3-OCF3, and compound 16 should be 4-OCF3.

Bubble coalescence and break-up have been studied in model pseudoplastic fluids (carbopol 934). The rates of coalescence and break-up have been determined in turbulent flows using high speed photography. The effects of liquid viscosity and intensity of turbulence on coalescence and breakup are examined both experimentally and theoretically. A theory for predicting the maximum stable particle size in turbulent pipe flows is presented that fits both our own bubble break-up data and liquid-liquid data obtained from the literature. Bubble coalescence was examined experimentally and found to be controlled by instabilities growing at the surface of the bubble. The effect of pseudoplasticity on surface instabilities is examined theoretically.