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Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling in melanoma phenotype switching
No full textIn melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFβ/SMAD, YAP/TAZ, and β-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of β-catenin, with YAP/TAZ governing an essential subprogram of TGFβ-induced phenotype switching. Wnt/β-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ-induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy
Pre-clinical in-vitro studies on parameters governing immune complex formation
No full textThe success of biotherapeutics is often challenged by the undesirable events of immunogenicity in patients, characterized by the formation of anti-drug antibodies (ADA). Under specific conditions, the ADAs recognizing the biotherapeutic can trigger the formation of immune complexes (ICs), followed by cascades of subsequent effects on various cell types. Hereby, the connection between the characteristics of ICs and their downstream impact is still not well understood. Factors governing the formation of ICs and the characteristics of these IC species were assessed systematically in-vitro. Classic analytical methodologies such as SEC-MALS and SV-AUC, and the state-of-the-art technology mass photometry were applied for the characterization. The study demonstrates a clear interplay between 1) the absolute concentration of the involved components, 2) their molar ratios, 3) structural features of the Biologic 4) and of its endogenous target. This surrogate study design is readily applicable to any biotherapeutic and provides valuable insights into mechanisms of IC formation prior to FIH studies. The applicability is versatile – from selection of candidates during developability assessment to evaluation of the impact of degraded or post-translationally modified biotherapeutics on the formation of ICs
Magic Rings: Navigation in the Ring Chemical Space Guided by the Bioactive Rings.
No full textThe large majority of bioactive molecules contain a more or less complex ring system as a central structural element. This central core determines the basic molecule shape, keeps substituents in their proper positions, and often also contributes to the biological activity itself. In this study the ring systems extracted from one billion molecules are processed and differences between rings from bioactive molecules and common synthetic molecules are analyzed. The bioactive rings seem to be distributed throughout the large portion of chemical space, but not uniformly; one can see several more dense regions, where the bioactive rings often appear in small clusters, as well as empty areas. A web tool offering an interactive navigation in the ring chemical space and supporting identification of bioisosteric ring analogs available at https://bit.ly/magicrings is also described
A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration.
No full textTo evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration.A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study.Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks.The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84.The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency.In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy
Impact of Aqueous Micellar Media on Biocatalytic Transformations Involving Transaminase (ATA); Applications to Chemoenzymatic Catalysis
No full textSurfactant-enabled asymmetric ATA-catalyzed reductive aminations in aqueous buffered media are described, representative of the enhanced levels of conversion made possible by the presence of a nonionic surfactant in the water, thereby minimizing enzymatic inhibition and enabling 1-pot chemoenzymatic catalysis. Several applications are described highlighting these modified conditions that involve both biocatalysis and chemocatalysis that are environmentally responsible, indicative of the possibilities using chemistry in water. Also included herein is technology for converting a racemic benzylic alcohol to a nonracemic primary amine, and an especially efficient synthesis of the pharmaceutical (S)-rivastigmine
Ring replacement recommender: Ring modifications for improving biological activity.
No full textAnalysis of structure-activity data from a large corpus of medicinal chemistry literature identified a set of ring replacements that have a significant chance of improved biological activity. A database of these replacements for 245 common heterocyclic rings is provided. Based on the analysis of the whole data set, 80 diverse substituted rings are suggested for use in an early stage of hit optimization and in the design of focused libraries with the goal to explore structure-activity relationships and quickly improve the biological activity of the explored series. An easy to use Ring Replacement Recommender web tool, allowing medicinal chemists to interactively explore the recommended ring substitutions, is available at https://bit.ly/ringreplacement
Predicting in vivo brain penetration using multitask graph neural networks
No full textThe blood-brain-barrier (BBB) is a semi-permeable interface, separating the central nervous system (CNS) from the blood stream. The physiological role of the BBB is to create a stable microenvironment for the CNS by tightly regulating the transport of molecules from the blood to the brain and vice versa. For early drug discovery teams, it can be critical to know if com-pounds are able to penetrate into the brain compartment. Generally, pre-clinical in vivo studies measuring the ratio of total and free brain and blood concentrations (Kp and Kpuu, respectively) are required to estimate the brain penetration potential of a new drug entitiy. In this work, we evaluated the performance of different machine learning approaches to predict Kp, using Novar-tis internal and publicly available experimental data. We investigated the benefit of including in vitro experimental data as auxiliary tasks in multitask graph neural network (MT-GNN) mod-els. We observed that MT-GNN models generally outperformed single-task (ST) learning ap-proaches, which were only trained on in vivo brain penetration data. The best performing MT-GNN regression model achieved a coefficient of determination (R2) of 0.42 on a prospective validation set and outperformed all tested ST models. Overall, models solely based on public data achieved lower performance on the prospective validation set compared to models built with internal data. However, the MT-GNN based upon literature data outperformed all litera-ture-based ST models, with a R2 of 0.31. Lastly, we observed that post hoc classification using a MT-GNN regression model outperformed a MT-GNN classification model, with Matthew’s correlation coefficient values of 0.66 and 0.44, respectively. Taken together, we show that the inclusion of the right auxiliary tasks improves the prediction of in vivo brain penetration using MT-GNNs
Bioinformatic Toolbox for the Development of novel CH-Activation Biocatalysts (CH-Pred)
No full textEnzymes are particularly well-suited catalysts for the site-specific C-H activation of active pharmaceutical intermediates. To accelerate enzyme development, an in silico screening workflow for the identification of active CH-activation enzymes will be developed and applied in product synthesis
A randomized clinical study evaluating the therapeutic equivalence of vildagliptin 100 mg once daily modified release to 50 mg twice daily immediate release formulations
No full textAims: Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor to treat type 2 diabetes mellitus, is available as immediate release (IR) tablets administered at 50 mg twice daily (BID). A 100 mg modified release (MR) formulation was developed for once daily (QD) dosing. This study aimed to compare the therapeutic equivalence of vildagliptin 100 mg MR QD (test) and 50 mg IR BID (reference) formulations at steady state under fasting conditions.
Methods: This was an open-label, randomized, two-period, single- and multiple-dose, two-way crossover, steady state study conducted in healthy adult subjects. Both vildagliptin formulations were administered for six days. Endpoints included pharmacodynamic equivalence, pharmacokinetic parameters, and tolerability of both formulations.
Results: Thirty subjects were enrolled and 26 completed both treatments. Maximum plasma concentration and exposure achieved with test was lower than reference formulation on day 1 and 6. The DPP-4 enzyme inhibition over time (DPP-4-AUEC0-24) was comparable between the formulations. Both formulations were well tolerated.
Conclusion: This study confirms the therapeutic equivalence of vildagliptin IR and MR formulations for DPP-4 enzyme inhibition over time. The study supports vildagliptin 100 mg MR QD as a useful therapeutic alternative to 50 mg IR BID formulation to possibly improve treatment adherence and patient compliance.
Keywords: Vildagliptin, Type 2 diabetes mellitus, Pharmacokinetic, Pharmacodynamic, Therapeutic equivalence, Treatment adherence and compliance, Dipeptidyl-peptidase IV inhibitor
The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease.
No full textWNT/β-catenin signaling plays pivotal roles during liver development, homeostasis, and regeneration. Likewise, its deregulation disturbs metabolic liver zonation and is responsible for the development of a large number of hepatic tumors. Liver fibrosis, which has become a major health burden for society and a hallmark of NASH, can also be promoted by WNT/β-catenin signaling. Upstream regulatory mechanisms controlling hepatic WNT/β-catenin activity may constitute targets for the development of novel therapies addressing these life-threatening conditions. The R-spondin (RSPO)-leucine-rich repeat-containing G protein-coupled receptor (LGR) 4/5-zinc and ring finger (ZNRF) 3/ring finger 43 (RNF43) module is fine-tuning WNT/β-catenin signaling in several tissues and is essential for hepatic WNT/β-catenin activity. In this review article, we recapitulate the role of the RSPO-LGR4/5-ZNRF3/RNF43 module during liver development, homeostasis, metabolic zonation, regeneration, and disease. We further discuss the controversy around LGR5 as a liver stem cell marker