Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation

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, B1-PEG, synthesized through PEGylation of an optimized PROTAC
molecule, B1, to enhance its properties. B1-PEG 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 B1-PEG’s
superior bioavailability at 84.8%, outperforming the unmodified PROTAC
molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG 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.