Structure-activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling.

The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes in these cells and in PDAC animal models. It is currently in Phase 1a clinical evaluation as an anticancer drug.

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling.

Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A.

The metastasis suppressor protein NME1 is an evolutionarily conserved and multifunctional enzyme that plays an important role in suppressing the invasion and metastasis of tumour cells. The nucleoside diphosphate kinase (NDPK) activity of NME1 is well recognized in balancing the intracellular pools of nucleotide diphosphates and triphosphates to regulate cytoskeletal rearrangement and cell motility, endocytosis, intracellular trafficking, and metastasis. In addition, NME1 was found to function as a protein-histidine kinase, 3'-5' exonuclease and geranyl/farnesyl pyrophosphate kinase.

Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion.

RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC of 1.

Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models.

Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetra-substituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and activity compared with previous ND compounds and nanomolar binding to human quadruplexes.

Substituted Naphthalenediimide Compounds Bind Selectively to Two Human Quadruplex Structures with Parallel Topology.

Interactions are reported of three representative naphthalenediimide derivatives with three quadruplex targets, from the promoter region of the telomerase (hTERT) gene, a human telomeric DNA quadruplex, and a telomeric RNA quadruplex (TERRA). Thermal melting studies showed that these compounds strongly stabilize the quadruplexes, with weak stabilization of a duplex DNA. Binding studies by surface plasmon resonance and fluorescence spectroscopy found that the compounds bind to the quadruplexes with nanomolar equilibrium dissociation constants.

Evasion of a Human Cytomegalovirus Entry Inhibitor with Potent Cysteine Reactivity Is Concomitant with the Utilization of a Heparan Sulfate Proteoglycan-Independent Route of Entry.

The dependence of viruses on the host cell to complete their replicative cycle renders cellular functions potential targets for novel antivirals. We screened a panel of broadly acting cellular ion channel inhibitors for activity against human cytomegalovirus (HCMV) and identified the voltage-gated chloride ion channel inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) as a potent inhibitor of HCMV replication. Time-of-addition studies demonstrated that DIDS inhibited entry via direct interaction with the virion that impeded binding to the plasma membrane.

Identification of Broad-Spectrum Antiviral Compounds by Targeting Viral Entry.

Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available.

Development and validation of RdRp Screen, a crystallization screen for viral RNA-dependent RNA polymerases.

Members of the family constitute a severe risk to human health. Whilst effective drugs have been developed against the HCV, no antiviral therapy is currently available for any other viruses, including the dengue (DENV), West Nile and Zika viruses. The RNA-dependent RNA polymerase (RdRp) is responsible for viral replication and represents an excellent therapeutic target with no homologue found in mammals.

Progress towards a public chemogenomic set for protein kinases and a call for contributions.

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases.

Tails of the Travelling Gaussian model and the relative age effect: Tales of age discrimination and wasted talent.

The Relative Age Effect (RAE) documents the inherent disadvantages of being younger rather than older in an age-banded cohort, typically a school- or competition-year, to the detriment of career-progression, earnings and wellbeing into adulthood. We develop the Tails of the Travelling Gaussian (TTG) to model the mechanisms behind RAE. TTG has notable advantages over existing approaches, which have been largely descriptive, potentially confounded, and non-comparable across contexts.

Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase.

Objectives: (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action.

Methods: Biomimetic Pictet-Spengler or Bischler-Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds.

The crystal structure of NS5A domain 1 from genotype 1a reveals new clues to the mechanism of action for dimeric HCV inhibitors.

New direct acting antivirals (DAAs) such as daclatasvir (DCV; BMS-790052), which target NS5A function with picomolar potency, are showing promise in clinical trials. The exact nature of how these compounds have an inhibitory effect on HCV is unknown; however, major resistance mutations appear in the N-terminal region of NS5A that include the amphipathic helix and domain 1. The dimeric symmetry of these compounds suggests that they act on a dimer of NS5A, which is also consistent with the presence of dimers in crystals of NS5A domain 1 from genotype 1b.

Sexual segregation and flexible mating patterns in temperate bats.

Social structure evolves from a trade-off between the costs and benefits of group-living, which are in turn dependent upon the distribution of key resources such as food and shelter. Males and females, or juveniles and adults, may have different priorities when selecting habitat due to differences in physiological or behavioural imperatives, leading to complex patterns in group composition. We studied social structure and mating behaviour in the insectivorous bat Myotis daubentonii along an altitudinal gradient, combining field studies with molecular genetics.

Development of a fluorescence intensity assay for the mitotic serine/threonine protein kinase Aurora-A.

The Aurora kinases are a group of serine/threonine protein kinases that regulate key steps during mitosis, and deregulation of these proteins (e.g., by gene amplification or overexpression) has been linked to a wide variety of tumor types.

Direct soil contact values for ecological receptors exposed to weathered petroleum hydrocarbon (PHC) fraction 2.

Ecological tier 1 Canada-wide standards (CWS) for petroleum hydrocarbon (PHC) fraction 2 (F2; >nC10-C16) in soil were derived using ecotoxicological assessment endpoints (effective concentrations [ECs]/lethal concentrations [LCs]/inhibitory concentrations, 25% [IC25s]) with freshly spiked (fresh) fine- and coarse-grained soils. These soil standards might be needlessly conservative when applied to field samples with weathered hydrocarbons. The purpose of the present study was to assess the degradation and toxicity of weathered PHC F2 in a fine-grained soil and to derive direct soil contact values for ecological receptors.

Fish oil supplementation maintains adequate plasma arachidonate in cats, but similar amounts of vegetable oils lead to dietary arachidonate deficiency from nutrient dilution.

Because fatty acid (FA) metabolism of cats is unique, effects of dietary fish and vegetable oil supplementation on plasma lipids, lipoproteins, lecithin/cholesterol acyl transferase activities, and plasma phospholipid and esterified cholesterol (EC) FAs were investigated. Cats were fed a commercial diet supplemented with 8 g oil/100 g diet for 4 weeks using either high-oleic-acid sunflower oil (diet H), Menhaden fish oil (diet M), or safflower oil (diet S). When supplemented, diet M contained sufficient arachidonate (AA), but diets H and S were deficient.

Age and sex differences in object control skills by children ages 5 to 14.

Object control skills provide children the tools to be physically active-a major societal priority. At the fundamental movement level, object control skills form the foundation of further sports skill development. The purpose of this study was to examine children's (ages 5 to 14 years, Grades K-8) development of four key object control skills: catching, throwing, kicking, and striking.

The prophylaxis and treatment with antiviral agents of respiratory syncytial virus infections.

In this review, we consider recent advances in the discovery and development of antiviral agents for respiratory syncytial virus (RSV) infections. A background to the various manifestations of human RSV infection and current treatments is provided. The technical, clinical and commercial issues surrounding the development of such antiviral agents are discussed.

Screening for EGFR and KRAS mutations in endobronchial ultrasound derived transbronchial needle aspirates in non-small cell lung cancer using COLD-PCR.

EGFR mutations correlate with improved clinical outcome whereas KRAS mutations are associated with lack of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) is being increasingly used in the management of NSCLC. Co-amplification at lower denaturation temperature (COLD)-polymerase chain reaction (PCR) (COLD-PCR) is a sensitive assay for the detection of genetic mutations in solid tumours.

Polychlorinated biphenyl elimination rates and changes in chemical activity in hibernating amphibians.

The present study examined polychlorinated biphenyl (PCB) elimination rates in overwintering green frogs (Rana clamitans) to determine if changes in chemical activity occurred during hibernation. Adult green frogs were dosed with a 1:1:1 ratio of Aroclors 1248:1254:1260 in sunflower oil and allowed to enter into hibernation. Frogs were collected at four time points over the course of 85 days.

Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy.

Purpose: Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies.

Methods: Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy.

Re-induction of obese body weight occurs more rapidly and at lower caloric intake in beagles.

For the purpose of investigating the mechanism of obesity-induction/re-induction including weight-cycling in beagles, a study was conducted using commercially available dog food combined with human food to mimic at home-snacking and diet-supplementation behaviours. Adult female beagles, which had free access to water and exercise, were used (n = 9). All dogs were initially offered two times their daily calculated number of calories using a dry extruded diet plus blend of canola and soybean oils and allowed to eat ad libitum.

Plasma LCAT activity and lipid subfraction composition in obese beagles undergoing weight loss.

The relationship between lecithin:cholesterol acyltransferase (LCAT) activity and weight loss in dogs was investigated. Four experimental weight-loss diets were fed to 12 obese female beagles for 56 days in a partial crossover design (n = 6). High- (HGI) or low- (LGI) glycemic index starch and diacylglycerol or triacylglycerol oils were combined to compose experimental diets with similar fatty acid profiles.

Biphenyl amide p38 kinase inhibitors 3: Improvement of cellular and in vivo activity.

The biphenyl amides (BPAs) are a novel series of p38alpha MAP kinase inhibitor. The optimisation of the series to give compounds that are potent in an in vivo disease model is discussed. SAR is presented and rationalised with reference to the crystallographic binding mode.