Covalent Drug Development: Mass Spectrometry and PK/PD Modeling

**This study introduces an innovative workflow for covalent drug development, addressing limitations like false positives and the disconnect between drug concentration and effect.** The core of this workflow is a mass spectrometry (MS) assay for measuring drug-target protein conjugation and an intact protein PK/PD model (iPK/PD) that determines pharmacokinetic and pharmacodynamic parameters from target engagement data. **A decision tree guides researchers through the process, from initial screening to in vivo studies.** The methods are applied to approved drugs like ibrutinib and sotorasib, various protein targets, and ALS drug candidates targeting SOD1. **The research demonstrates the assay's ability to improve covalent drug candidate selection and demonstrates the evolution toward reduced off-target binding to serum albumin in more recent covalent drugs.** Ultimately, this framework offers a new means of evaluating covalent drugs. - Google NotebookLM Publication: https://www.nature.com/articles/s41467-025-56985-6#Sec35