Beyond Internalization: Target Binding as the Trigger.

Binding-to-release (BTR) strategy enables target engagement to trigger payload release, demonstrated with 15 optimized PhoPEx compounds for improved tumor drug exposure.

• Why it matters: Current targeted drug conjugates depend on internalization, limiting the range of exploitable tumor-associated targets, especially poorly internalizing ones, which restricts therapeutic options.
• What they did: Wen and colleagues developed a ligand-directed PhoPEx chemistry that exploits proximity between an electrophilic linker and a tyrosine residue in the target binding pocket, testing it on fibroblast activation protein and other targets.
• The result: The BTR strategy improved tumor drug exposure and antitumor activity in preclinical models, and was extended to imaging and other targets, potentially broadening targeted therapeutic approaches.