30DC

T2R-TTL-compound 40 complex

This is a non-PDB format compatible entry.

Summary for 30DC

• Entry DOI: 10.2210/pdb30dc/pdb
• Descriptor: Tubulin alpha-1B chain, 2-[bis(fluoranyl)methoxy]-~{N}-[[3-(2-methoxyphenyl)-1~{H}-1,2,4-triazol-5-yl]methyl]benzamide, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 265214.89

Authors

Prota, A.E.,Steinmetz, M.O.,Vishnudas, V.K. (deposition date: 2026-04-21, release date: 2026-11-04)

Primary citation

Chimmanamada, D.,Nastke, M.D.,Ravi, A.,Matson, J.P.,Batrouni, A.G.,Mota, A.L.,Pozo, P.N.,Grund, E.M.,Smith, M.D.,Abel, A.C.,Kendirli, M.T.,Smith, J.C.,Recht, L.,Narain, N.R.,Gesta, S.,Steinmetz, M.O.,Prota, A.E.,Vishnudas, V.K.
Discovery and Optimization of a Novel Brain-Penetrant Colchicine-Binding Site Ligand for Treatment of Glioma.
J.Med.Chem., 69:24150-24167, 2026

PubMed Abstract: 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.

PubMed: 42911726
DOI: 10.1021/acs.jmedchem.6c01659

Experimental method

X-RAY DIFFRACTION (2.64 Å)