Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC of 282.

Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.

Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine kinases and form a subfamily of the protein kinase AMP-activated protein kinase (AMPK) family. Inhibition of SIKs in stimulated innate immune cells and mouse models has been associated with a dual mechanism of action consisting of a reduction of pro-inflammatory cytokines and an increase of immunoregulatory cytokine production, suggesting a therapeutic potential for inflammatory diseases. Following a high-throughput screening campaign, subsequent hit to lead optimization through synthesis, structure-activity relationship, kinome selectivity, and pharmacokinetic investigations led to the discovery of clinical candidate GLPG3312 (compound ), a potent and selective pan-SIK inhibitor (IC: 2.

Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel.

Identification and Characterization of Novel CFTR Potentiators.

There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators.

PI4KIII inhibitor enviroxime impedes the replication of the hepatitis C virus by inhibiting PI3 kinases.

Objectives: Many positive-stranded RNA viruses, including HCV, drastically remodel intracellular membranes to generate specialized environments for RNA replication. Phosphatidylinositol 4-kinase III (PI4KIII)α plays an essential role in the formation of HCV replication complexes and has therefore been explored as a potential drug target. Here, we characterized the anti-HCV activity of the PI4KIII inhibitors enviroxime and BF738735 and elucidated their mechanism of action.

Treatment plan quality and delivery accuracy assessments on 3 IMRT delivery methods of stereotactic body radiotherapy for spine tumors.

Stereotactic body radiotherapy (SBRT) for spine tumors has demonstrated clinical effectiveness. The treatment planning and delivery techniques have evolved from dynamic conformal arc therapy, to fixed gantry angle intensity modulated radiotherapy (IMRT), and most recently to volumetric modulated arc therapy (VMAT). A hybrid-arc (HARC) planning and delivery method combining dynamic conformal arc therapy delivery with a number of equally spaced IMRT beams is proposed.

Dosimetric effect of uncorrected rotations in lung SBRT with stereotactic imaging guidance.

Purpose: To evaluate the dosimetric impact of uncorrected rotations on the planning target volume (PTV) coverage for early stage non-small cell lung cancer patients treated with stereotactic body radiotherapy using Brainlab ExacTrac image guidance.

Methods: Twenty-two patients were retrospectively selected. Two scenarios of uncorrected rotations were simulated with magnitude of 1°, 2°, 3° and 5°: (1) rotation around the treatment isocenter; and (2) roll and yaw rotations around a setup isocenter.

Discovery of N-(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent.

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators).

Three cases of imported eyeworm infection in dogs: a new threat for the United Kingdom.

In July 2016 we described the first known case of canine ocular thelaziosis in the UK in a dog recently imported from Romania. Here we confirm our initial diagnosis using PCR followed by sequence analysis, and we report a further two clinical cases in dogs with recent history of travel to Italy and France. In view of the presence in the UK of the vector for , namely spp, we discuss the significance of these three cases in the context of the UK government's pet travel scheme, disease control and both animal and public health in the UK.

A Histologic Basis for the Efficacy of SBRT to the lung.

Purpose: Stereotactic body radiation therapy (SBRT) is the standard of care for medically inoperable patients with early-stage NSCLC. However, NSCLC is composed of several histological subtypes and the impact of this heterogeneity on SBRT treatments has yet to be established.

Methods: We analyzed 740 patients with early-stage NSCLC treated definitively with SBRT from 2003 through 2015.

A Treatment Planning Study of Stereotactic Body Radiotherapy for Atrial Fibrillation.

Purpose:  To explore the feasibility of using stereotactic body radiotherapy (SBRT) to irradiate the antra of the four pulmonary veins while protecting nearby critical organs, such as the esophagus.

Materials And Methods:  Twenty patients who underwent radiofrequency catheter ablation for atrial fibrillation were selected. For each patient, the antra of the four pulmonary veins were identified as the target volumes on a pre-catheterization contrast or non-contrast CT scan.

Forecast cooling of the Atlantic subpolar gyre and associated impacts.

Decadal variability in the North Atlantic and its subpolar gyre (SPG) has been shown to be predictable in climate models initialized with the concurrent ocean state. Numerous impacts over ocean and land have also been identified. Here we use three versions of the Met Office Decadal Prediction System to provide a multimodel ensemble forecast of the SPG and related impacts.

Manganese-enhanced MRI detection of impaired calcium regulation in a mouse model of cardiac hypertrophy.

The aim of this study was to use manganese (Mn)-enhanced MRI (MEMRI) to detect changes in calcium handling associated with cardiac hypertrophy in a mouse model, and to determine whether the impact of creatine kinase ablation is detectable using this method. Male C57BL/6 (C57, n = 11) and male creatine kinase double-knockout (CK-M/Mito(-/-) , DBKO, n = 12) mice were imaged using the saturation recovery Look-Locker T1 mapping sequence before and after the development of cardiac hypertrophy. Hypertrophy was induced via subcutaneous continuous 3-day infusion of isoproterenol, and sham mice not subjected to cardiac hypertrophy were also imaged.

Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.

Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections.

Fitness and virulence of a coxsackievirus mutant that can circumnavigate the need for phosphatidylinositol 4-kinase class III beta.

Coxsackieviruses require phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) for replication but can bypass this need by an H57Y mutation in protein 3A (3A-H57Y). We show that mutant coxsackievirus is not outcompeted by wild-type virus during 10 passages in vitro. In mice, the mutant virus proved as virulent as wild-type virus, even when mice were treated with a PI4KIIIβ inhibitor.

A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIβ.

Despite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM.

Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis.

MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.

Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design.

Peptides that inhibit cyclin-dependent kinase 2 by blocking the macromolecular substrate recruitment site of cyclin A were simplified, for example, by replacement of dipeptide units with beta-amino acids. The smallest inhibitor retaining activity was a tripeptide, whose binding mode was confirmed by X-ray crystallography. This result suggests that nonpeptidic cyclin groove inhibitors may be feasible therapeutic agents.

REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors.

We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants.

Expediting drug discovery: recent advances in fast medicinal chemistry--optimization of hits and leads.

This article reviews the literature from January 2004 to January 2006 relating to the use of parallel chemistry compound libraries in drug discovery. Examples of libraries that have yielded active compounds across a range of biological targets are presented, together with synthetic details where relevant. The background of the biological target, and any structure-activity relationship that can be discerned from members of a library series, are also commented upon.

Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes.

Inhibition of cyclin A- and cyclin E-associated cyclin-dependent kinase-2 (CDK2) activities is an effective way of selective induction of apoptotic cell death via the E2F pathway in tumour cells. The cyclin groove recognition motif (CRM) in the natural CDK-inhibitory (CDKI) tumour suppressor protein p27KIP1 was used as the basis for the design and synthesis of a series of cyclic peptides whose biological activity and structural characterisation by NMR and X-ray crystallography is reported. Whereas linear p27KIP1 sequence peptides were comparatively ineffective, introduction of side chain-to-tail constraints was found to be productive.

Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange.

Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity through blocking of the substrate recognition site in the cyclin A subunit has been demonstrated to be an effective method for inducing apoptosis in tumor cells. We have used the cyclin binding motif (CBM) present in the tumor suppressor proteins p21(WAF1) and p27(KIP1) as a template to optimize the minimal sequence necessary for CDK2/CA inhibition. A series of peptides were prepared, containing nonnatural amino acids, which possess nano- to micromolar CDK2-inhibitory activity.