Brain-penetrant colchicine-site tubulin ligand nominated for glioma
- Only temozolomide and vorasidenib are approved brain-permeable, orally available drugs for brain cancers, so the team sought new brain-penetrant options.
- SAR work yielded a new class of highly brain-penetrant tubulin ligands; co-crystal structures confirm colchicine-site binding, with the tubulin βT7 and αT5 loops flipped relative to the colchicine-bound state.
- SAR showed high sensitivity to substitution with few indispensable moieties, leading to compound 40 as the clinical candidate.
💡 Points
Tubulin binders that actually cross the blood-brain barrier usually die on P-gp efflux or neurotoxicity, so a tight series with strong brain exposure is notable. The flipped βT7/αT5 loops hint at a binding mode worth docking my own colchicine-site scaffolds against. Chronic neurotoxicity is still the question.