Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation

Abstract

Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, <b>B1-PEG</b>, synthesized through PEGylation of an optimized PROTAC molecule, <b>B1</b>, to enhance its properties. <b>B1-PEG</b> is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed <b>B1-PEG</b>'s superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule <b>B1</b>. When tested in a H3122 xenograft mouse model, <b>B1-PEG</b> significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.