6QQN

Tubulin-TH588 complex

Summary for 6QQN

• Entry DOI: 10.2210/pdb6qqn/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, N~4~-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine, ... (13 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: 264903.60

Authors

Patterson, J.C.,Joughin, B.A.,Prota, A.E.,Muehlethaler, T.,Jonas, O.H.,Whitman, M.A.,Varmeh, S.,Chen, S.,Balk, S.P.,Steinmetz, M.O.,Lauffenburger, D.A.,Yaffe, M.B. (deposition date: 2019-02-18, release date: 2019-07-24, Last modification date: 2024-01-24)

Primary citation

Patterson, J.C.,Joughin, B.A.,Prota, A.E.,Muhlethaler, T.,Jonas, O.H.,Whitman, M.A.,Varmeh, S.,Chen, S.,Balk, S.P.,Steinmetz, M.O.,Lauffenburger, D.A.,Yaffe, M.B.
VISAGE Reveals a Targetable Mitotic Spindle Vulnerability in Cancer Cells.
Cell Syst, 9:74-92.e8, 2019

PubMed Abstract: There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying synergistic mechanism, we developed VISAGE, a strategy integrating experimental synergy quantification with computational-pathway-based gene expression analysis. VISAGE predicted, and we experimentally confirmed, that this synergistic combination treatment targeted the mitotic spindle. Specifically, TH588 binding to β-tubulin impaired microtubule assembly, which when combined with Plk1 blockade, synergistically disrupted mitotic chromosome positioning to the spindle midzone. These findings identify a cancer-specific mitotic vulnerability that is targetable using Plk1 inhibitors with microtubule-destabilizing agents and highlight the general utility of the VISAGE approach to elucidate molecular mechanisms of drug synergy.

PubMed: 31302152
DOI: 10.1016/j.cels.2019.05.009

Experimental method

X-RAY DIFFRACTION (2.301 Å)