Zanubrutinib: A Comprehensive Hybrid Review of its Design, Synthesis, Physicochemical Properties, and Therapeutic Applications with Comparative In Silico ADMET and Toxicity Profiling

Abstract

Recent advances in Bruton tyrosine kinase (BTK) inhibition have significantly improved the management of B-cell malignancies. Following the success of Ibrutinib as the first approved BTK inhibitor, Zanubrutinib emerged as a next-generation inhibitor designed to achieve greater selectivity, improved enzymatic activity, and better pharmacokinetic properties. Preclinical studies demonstrated enhanced specificity and bioavailability compared with earlier BTK inhibitors, supporting its further clinical development. Subsequent clinical trials confirmed its efficacy in several B-cell malignancies, along with a more favorable safety profile that is likely related to reduced off-target effects. Today, Zanubrutinib is approved in multiple countries for the treatment of various B-cell cancers and continues to be investigated in broader therapeutic settings and combination strategies. To complement the review of its molecular design, synthesis, and clinical applications, we performed a comparative in silico ADMET and toxicity evaluation of Zanubrutinib alongside Ibrutinib and Acalabrutinib. Computational profiling confirms Zanubrutinib's optimal drug-likeness, demonstrating zero Lipinski and Veber rule violations alongside high gastrointestinal absorption (95.4%). Crucially, predictive screening assigns Zanubrutinib to Toxicity Class 4 (LD50 = 1000 mg/kg), highlighting a safer acute toxicity profile compared to Acalabrutinib (Class 3, LD50 = 135 mg/kg). Ultimately, these theoretical findings strongly corroborate the favorable pharmacokinetic behavior and enhanced safety profile observed in clinical settings. A bibliometric analysis is conducted using Scopus and VOSviewer.