Unveiling Pralsetinib As Selective RET Inhibitor for Precision Oncology: An In Silico ADMET and Toxicity Study

Abstract

Pralsetinib is a highly selective, orally administered RET tyrosine kinase inhibitor targeting oncogenic fusions and mutations in thyroid and non-small-cell lung cancer (NSCLC). Its nitrogen-rich heteroaromatic framework, synthesized via a scalable palladium-catalyzed process, provides superior target selectivity and safety over earlier multikinase inhibitors. To complement its established clinical profile, we performed a comprehensive in silico ADMET and toxicity evaluation comparing Pralsetinib with Selpercatinib and Vandetanib. Computational analysis revealed a favorable pharmacokinetic profile; notably, Pralsetinib does not inhibit major cytochromes (CYP2D6 and CYP3A4), significantly reducing the risk of drug-drug interactions. Moreover, predictive screening assigned Pralsetinib to Toxicity Class 4 (LD50= 800 mg/kg), demonstrating a safer acute toxicity profile than Selpercatinib (Class 3). Overall, these findings consolidate Pralsetinib's therapeutic potential and safety as a prime example of biomarker-driven precision oncology