Discovery of a Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) Inhibitor Suitable for Clinical Progression

Abstract Protein kinase R-like endoplasmic reticulum kinase (PERK) is a key sensor in the integrated stress response (ISR) and the unfolded protein response (UPR), playing a critical role in tumor cell survival under stress conditions. Based on literature data, we identified the novel PERK inhibitor 17, of moderate potency but promising kinase selectivity and in vivo pharmacokinetics. A lead optimisation campaign focussing on careful control of lipophilicity (log D) and lipophilic ligand efficiency (LLE) led to the identification of 49 (APL-11056), a potent and selective PERK inhibitor. High permeability contributes to its excellent in vivo pharmacokinetics and can be linked to the presence of a fluorine alpha to the core benzamide, which limits recognition by efflux transporters.