A Comparative Clinical Pharmacology Analysis of FDA-Approved Targeted Covalent Inhibitors vs. Reversible Inhibitors in Oncology.

Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mechanism is anticipated to elicit the following theoretical benefits: (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life, (ii) a lower therapeutic dose owing to greater pharmacological potency, (iii) lower risk of off-target binding and associated adverse events, and (iv) reduced drug-drug interaction (DDI) liability due to high selectivity and low dose.

Social stress-potentiated methamphetamine seeking.

Human studies of substance use disorder show that psychological stress and drug availability interact following rehabilitation, contributing to the high relapse potential. Social stressors trigger particularly strong motivation for drug, but how this affects neuronal function to increase relapse is unknown. Animal models, which allow for the dissection of neural mechanisms, primarily utilize physical stressors to trigger relapse.