Verubulin repurposed as a dual-action ADC payload that hits tubulin and tumour vasculature
- Verubulin, which inhibits tubulin and disrupts tumour vasculature, was explored as a new antibody-drug conjugate payload to broaden the limited range of cytotoxic mechanisms.
- Amide- or carbamate-linked conjugates were unstable and weakly active, but a quaternary-ammonium linkage gave stable conjugates with very potent, target-dependent killing and little bystander effect.
- In mice the ADCs shrank tumours, were well tolerated and held growth in check longer than bevacizumab, yet remained less effective than T-DM1 and T-DXd.
💡 Points Based on the abstract
Verubulin is a colchicine-site binder with a basic quinazoline core, so the quaternary-ammonium trick makes sense: the tertiary amine is the natural handle, and quaternizing it avoids amide and carbamate linkers that kill potency. The catch is release. If the payload comes off as a charged species, low bystander effect is predictable, and that limits use in heterogeneous tumours. Still, a non-auristatin, non-maytansinoid tubulin payload adds welcome diversity.