Theory of Rayleigh-Brillouin optical activity light scattering applicable to chiral liquids.

It has long been understood that dilute samples of chiral molecules such as rarefied gases should exhibit Rayleigh optical activity. We extend the existing theory by accounting for molecular dynamics and correlations, thus obtaining a more general theory of Rayleigh-Brillouin optical activity applicable to dense samples such as neat liquids.

Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.

RAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization.

A Novel Small-Molecule Inhibitor of MRCK Prevents Radiation-Driven Invasion in Glioblastoma.

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that causes severe neurologic, cognitive, and psychologic symptoms. Symptoms are caused and exacerbated by the infiltrative properties of GBM cells, which enable them to pervade the healthy brain and disrupt normal function. Recent research has indicated that although radiotherapy (RT) remains the most effective component of multimodality therapy for patients with GBM, it can provoke a more infiltrative phenotype in GBM cells that survive treatment.

Discovery of Potent and Selective MRCK Inhibitors with Therapeutic Effect on Skin Cancer.

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here, we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphologic changes in cancer cells along with inhibition of their motility and invasive character.

Gap enhanced fluorescence as a road map for the detection of very weakly fluorescent emitters from visible to ultraviolet.

We analyze the enhancement of the rates of both the emission and the far field radiation for dipoles placed in the gap between a metallic nanorod, or nanosphere, and a metallic substrate. For wavelengths between 150 nm and 650 nm, the response of the gapped nanostructures considered in this work is dominated by few principal modes of the nanoparticle, which include self-consistently the effect of the substrate. For wavelengths shorter than 370 nm, the far field radiative enhancements of aluminum nanostructures are significantly higher than those for gold or silver.

Enhancing ultraviolet spontaneous emission with a designed quantum vacuum: erratum.

We present a correction to parts of Fig. 5, Fig. 6 and Fig.

Enhancing ultraviolet spontaneous emission with a designed quantum vacuum.

We determine how to alter the properties of the quantum vacuum at ultraviolet wavelengths to simultaneously enhance the spontaneous transition rates and the far field detection rate of quantum emitters. We find the response of several complex nanostructures in the 200 - 400 nm range, where many organic molecules have fluorescent responses, using an analytic decomposition of the electromagnetic response in terms of continuous spectra of plane waves and discrete sets of modes. Coupling a nanorod with an aluminum substrate gives decay rates up to 2.

Dataset on coherent control of fields and induced currents in nonlinear multiphoton processes in a nanosphere.

We model a scheme for the coherent control of light waves and currents in metallic nanospheres which applies independently of the nonlinear multiphoton processes at the origin of waves and currents. Using exact mathematical formulae, we calculate numerically with a custom fortran code the effect of an external control field which enable us to change the radiation pattern and suppress radiative losses or to reduce absorption, enabling the particle to behave as a perfect scatterer or as a perfect absorber. Data are provided in tabular, comma delimited value format and illustrate narrow features in the response of the particles that result in high sensitivity to small variations in the local environment, including subwavelength spatial shifts.

Coherent control of radiation patterns of nonlinear multiphoton processes in nanoparticles.

We propose a scheme for the coherent control of light waves and currents in metallic nanospheres which applies independently of the nonlinear multiphoton processes at the origin of waves and currents. We derive conditions on the external control field which enable us to change the radiation pattern and suppress radiative losses or to reduce absorption, enabling the particle to behave as a perfect scatterer or as a perfect absorber. The control introduces narrow features in the response of the particles that result in high sensitivity to small variations in the local environment, including subwavelength spatial shifts.

A novel small-molecule MRCK inhibitor blocks cancer cell invasion.

Background: The myotonic dystrophy kinase-related CDC42-binding kinases MRCKα and MRCKβ regulate actin-myosin contractility and have been implicated in cancer metastasis. Along with the related ROCK1 and ROCK2 kinases, the MRCK proteins initiate signalling events that lead to contractile force generation which powers cancer cell motility and invasion. A potential strategy for cancer therapy is to reduce metastasis by blocking MRCK activity, either alone or in combination with ROCK inhibition.

Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles.

Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.

Identification of potent, soluble, and orally active TRPV1 antagonists.

Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists.

Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists.

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.

Design, synthesis, and structure-activity relationships of indole-3-heterocycles as agonists of the CB1 receptor.

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo.

Rapid access towards follow-up NOP receptor agonists using a knowledge based approach.

A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.