7196 research outputs found
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Ligand-Free Regioselective Aromatic Hydrogenation of Phosphine Oxide Scaffolds: An Easy Access to New Phosphine Ligands
No full textHerein, we described the first semi- and regioselective hydrogenation of P(V)-substituted naphthalenes. This ligand-free iridium-catalyzed reaction delivers phosphine oxides or phosphonates in almost quantitative yields and with total regioselectivity. This report also exposed a novel pathway toward the preparation of H8-BINAP ligands derivatives. The importance of HFIP solvent is also evidenced by 1H-NMR experiments. Catalyst analysis also demonstrated the involvement of ultrasmall iridium(0) nanoparticles and the potential recycling of the catalyst was also showcase
Explaining compound activity predictions with a substructure-aware loss for graph neural networks.
No full textExplainable machine learning is increasingly used in drug discovery to help rationalize compound property predictions. Feature attribution techniques are popular choices to identify which molecular substructures are responsible for a predicted property change. However, established molecular feature attribution methods have so far displayed low performance for popular deep learning algorithms such as graph neural networks (GNNs), especially when compared with simpler modeling alternatives such as random forests coupled with atom masking. To mitigate this problem, a modification of the regression objective for GNNs is proposed to specifically account for common core structures between pairs of molecules. The presented approach shows higher accuracy on a recently-proposed explainability benchmark. This methodology has the potential to assist with model explainability in drug discovery pipelines, particularly in lead optimization efforts where specific chemical series are investigated
Safe and effective treatments are needed for cryptosporidiosis, a truly neglected tropical disease.
No full textNo abstrac
Re-evaluating the need for chronic toxicity studies with therapeutic monoclonal antibodies, using a weight of evidence approach
No full textTo support registration of monoclonal antibodies (mAbs) for chronic indications, 6-month toxicity studies have historically been conducted. Experience with mAb development has shown a relatively benign and well-understood safety profile for this class, with most toxicity findings anticipated based on pharmacology. We evaluated whether a 6-month toxicity study is optimal to assess the long-term safety of mAbs. Data on First-in-Human (FIH)-enabling and chronic toxicity studies were shared for 142 mAbs submitted by 11 companies. Opportunities to further optimize study designs to reduce animal usage were identified. For 71% of mAbs, no toxicities or no new toxicities were noted in chronic studies compared to FIH-enabling study findings. New toxicities of potential concern for human safety or that changed trial design were identified in 13.5% of cases, with 7% being considered critical and 2% leading to program termination. An iterative, weight-of-evidence model which considers factors that influence the overall risk for a mAb to cause toxicity was developed. This model enables an evidence-based justification, suggesting when 3-month toxicity studies are likely sufficient to support late-stage clinical development and registration for some mAbs
Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands.
No full textProprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting the degradation of hepatic LDL receptors (LDLRs). Current therapeutic approaches use antibodies that disrupt PCSK9 binding to LDLR to reduce circulating LDL-C concentrations or siRNA that reduces PCSK9 synthesis and thereby levels in circulation. Recent reports describe small molecules that, like therapeutic antibodies, interfere with PCSK9 binding to LDLR. We report an alternative approach to decrease circulating PCSK9 levels by accelerating PCSK9 clearance and degradation using heterobifunctional molecules that simultaneously bind to PCSK9 and the asialoglycoprotein receptor (ASGPR). Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation
People of TM: Video Data Science Academy Fellows
No full textThe video will be used for an external social media engagement campaign on platforms like you-tube, linked-in, facebook etc. featruing stories of people in TM. No IP related content
Efficacy and safety of remibrutinib, a selective, potent oral BTK inhibitor, in Sjögren’s syndrome
No full textObjectives To evaluate the safety and efficacy of remibrutinib in patients with moderate to severe SjS in a Phase 2 randomised, double-blind, trial.
Methods Eligible patients (moderate to severe SjS [classification according to 2016 ACR/ /European League Against Rheumatism (EULAR) criteria]; EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI] (based on weighted score) ≥ 5, EULAR Sjögren’s Syndrome Patient Reported Index [ESSPRI] ≥ 5; unstimulated salivary flow rate of > 0 mL/min) received remibrutinib (100 mg) either once or twice daily, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at Week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles.
Results Remibrutinib significantly improved ESSDAI score in SjS patients over 24 weeks compared with placebo (ΔESSDAI −2.86, P=0.003). No treatment effect was observed in ESSPRI score. There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Post-hoc analysis showed a strong effect on Sjögren’s Tool for Assessing Response (STAR) at 24 weeks in the remibrutinib groups. Remibrutinib induced significant changes in gene expression in blood as well as in serum protein abundance compared with placebo.
Conclusions These data show preliminary efficacy and favorable safety of remibrutinib in a Ph2 trial for SjS
Prediction of pharmacokinetics of an anaplastic lymphoma kinase inhibitor in rat and monkey: application of physiologically based pharmacokinetic model as an alternative tool to minimise animal studies.
No full textThe pharmacokinetic (PK) and toxicokinetic profile of a drug from its preclinical evaluation helps the researcher determine whether the drug should be tested in humans based on its safety and toxicity.Preclinical studies require time and resources and are prone to error. Moreover, according to the United States Food and Drug Administration Modernisation Act 2, animal testing is no longer mandatory for new drug development, and an animal-free alternative, such as cell-based assay and computer models, can be used.Different physiologically based PK models were developed for an anaplastic lymphoma kinase inhibitor in rats and monkeys after intravenous and oral administration using its physicochemical properties and in vitro characterisation data.The developed model was validated against the in vivo data available in the literature, and the validation results were found within the acceptable limit. A parameter sensitivity analysis was performed to identify the properties of the compound influencing the PK profile.This work demonstrates the application of the physiologically based PK model to predict the PKs of a drug, which will eventually assist in reducing the number of animal studies and save time and cost of drug discovery and development
MCS: What's new
No full textThis is only a brief summary, in form of a commented Jupyter Notebook, of the new MCS functionality that will be added in the new 2023.09 RDKit release.
This is going to be published as blog post on the RDKit blog (https://greglandrum.github.io/rdkit-blog/)
Non-labelled, Stable Labelled or Radiolabelled Approaches for Provision of Intravenous Pharmacokinetics in Humans: a Discussion Piece.
No full textA review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (IV PK) data provision is presented. The extent of application of the varied approaches available and the relative merits of each are highlighted with the aim of assisting practitioners in making informed decisions on the most scientifically appropriate design to adopt for any given new drug in development. It is envisaged that significant efficiencies will be realized as IV PK data in humans becomes more routinely available for suitable assets in early development, than has been the case prior to the last decade