Preclinical and Clinical Efficacy of Promising DprE1 Inhibitors: A Critical Review

ABSTRACT This review examines the clinical efficacy of DprE1 inhibitors, addressing the ongoing global challenge of tuberculosis (TB), particularly in the face of rising drug resistance. It critically discusses recent updates on clinically tested DprE1 inhibitors, including BTZ‐043, macozinone, quabodepistat (QBS), and TBA‐7371. These inhibitors have demonstrated potent DprE1 inhibitory activity and show significant promise against drug‐resistant TB strains in both preclinical and clinical studies. Notably, there has been increased interest in DprE1 inhibitors following the COVID‐19 pandemic. The primary focus is on their preclinical profile, resistance development, clinical efficacy, safety, and tolerability as monotherapies and in various combination regimens. Furthermore, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are analyzed in detail. However, several challenges, including off‐target effects, resistance development, solubility issues, and funding constraints, have hindered the clinical progress of some compounds. Despite these hurdles, DprE1 inhibitors hold significant potential to transform TB treatment. To fully realize their therapeutic potential, coordinated efforts are required to overcome existing barriers and strengthen the drug development pipeline.