Preclinical mitigation of 5-HT2B agonism-related cardiac valvulopathy revisited.

Cardiac valvulopathy (Cardiac Valve Disease; CVD) associated with off-target activation of the 5-hydroxytryptamine (5-HT) 2B receptor has been well recognized, but is still poorly predicted during drug development. The regulatory guidance proposes the use of 5-HT2B binding data (i.e., Ki values) and free maximum therapeutic exposure (Cmax) to calculate safety margins as a threshold of detection (>10) for eliminating the risk of drug-induced cardiac valvulopathy. In this paper, we provide additional recommendations for preclinical prediction of CVD risk based on clinical pharmacodynamic and pharmacokinetic data obtained from drugs with or without 5-HT2B receptor activation. Our investigations showed that 5-HT2B agonist affinity of molecules tested in an in vitro 5-HT2B cell-based functional assay, placed in perspective to their sustained plasma exposure (AUCs) and not to their peak plasma exposure, Cmax (i.e., maximum therapeutic exposure) provide a solid basis for interpreting 5-HT2B data, for calculating safety margins and then, accurately differentiate drugs associated with a clinical risk of CVD from those which are not (despite having some agonist 5-HT2B activity). In addition, we discuss the risk of multi-organ fibrosis linked to 5-HT2B receptor activation, often underestimated, however well reported in FAERS for 5-HT2B agonists. We believe that our recommendations have the potential to mitigate the risk for the clinical development of CVD and fibrosis.

Optimization of a Class of Dihydrobenzofurane Analogs toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors.

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.

Republished: A straightforward guide to the basic science behind arrhythmogenesis.

The underlying mechanisms behind cardiac arrhythmias are described in this manuscript. In clinical practice, significant arrhythmias are unpredictable, and under some conditions, potentially life-threatening. How can basic science help improve our understanding of molecular entities and factors behind the arrhythmia to advance, develop, adapt or deliver available medications? Structural heart disease and remodelling (e.g., heart failure, cardiomyopathy), the presence of modulating factors (i.e., diabetes mellitus, autonomic nervous system), genetic predispositions (i.e., channelopathies) are considerable preconditions, and influence the development of an arrhythmia. Cardiac arrhythmias may indeed share common basic mechanisms, while elements and substrates perpetuating these may be different and ultimately manifest as various ECG abnormalities. This article lists cellular and subcellular iatrogenic disorders responsible for abnormal impulse generation, or conduction disturbances, including the latest development in theories and biological research, for a better understanding of cellular disorders behind arrhythmogenesis.

A straightforward guide to the basic science behind arrhythmogenesis.

The underlying mechanisms behind cardiac arrhythmias are described in this manuscript. In clinical practice, significant arrhythmias are unpredictable, and under some conditions, potentially life-threatening. How can basic science help improve our understanding of molecular entities and factors behind the arrhythmia to advance, develop, adapt or deliver available medications? Structural heart disease and remodelling (eg, heart failure, cardiomyopathy), the presence of modulating factors (ie, diabetes mellitus, autonomic nervous system), genetic predispositions (ie, channelopathies) are considerable preconditions, and influence the development of an arrhythmia. Cardiac arrhythmias may indeed share common basic mechanisms, while elements and substrates perpetuating these may be different and ultimately manifest as various ECG abnormalities. This article lists cellular and subcellular iatrogenic disorders responsible for abnormal impulse generation, or conduction disturbances, including the latest development in theories and biological research, for a better understanding of cellular disorders behind arrhythmogenesis.