Discovery and Optimization of a Novel Brain-Penetrant Colchicine-Binding Site Ligand for Treatment of Glioma

The limited number of approved drugs for treatment of brain cancers is very apparent. Temozolomide and Vorasidenib continue to be the only approved brain-permeable, orally available drugs. A novel class of highly brain-penetrant tubulin-binding ligands was discovered through rigorous structure-activity-relationship (SAR) studies. The lead compounds were validated through tubulin polymerization assays and co-crystallization, demonstrating destabilization of microtubules by binding to the colchicine site of tubulin. The ligands maintain core interactions with tubulin like those of colchicine; however, both the tubulin βT7 and αT5 loops adopt flipped conformations compared with the colchicine-bound state. SAR studies revealed high selectivity for substitutions, with a small number of indispensable moieties, and led to the selection of small-molecule compound 40 as the clinical candidate. Compound 40 is highly potent, has high gut and moderate brain permeability, a favorable clearance and cytochrome P450 inhibition/induction profile, and demonstrated activity in models of glioma.