5sb5

Publication Abstract from PubMed

In this study, we capitalized on our previously performed crystallographic fragment screen and developed the antitubulin small molecule Todalam with only two rounds of straightforward chemical synthesis. Todalam binds to a novel tubulin site, disrupts microtubule networks in cells, arrests cells in G2/M, induces cell death, and synergizes with vinblastine. The compound destabilizes microtubules by acting as a molecular plug that sterically inhibits the curved-to-straight conformational switch in the alpha-tubulin subunit, and by sequestering tubulin dimers into assembly incompetent oligomers. Our results describe for the first time the generation of a fully rationally designed small molecule tubulin inhibitor from a fragment, which displays a unique molecular mechanism of action. They thus demonstrate the usefulness of tubulin-binding fragments as valuable starting points for innovative antitubulin drug and chemical probe discovery campaigns.

Rational Design of a Novel Tubulin Inhibitor with a Unique Mechanism of Action.,Muhlethaler T, Milanos L, Ortega JA, Blum TB, Gioia D, Roy B, Prota AE, Cavalli A, Steinmetz MO Angew Chem Int Ed Engl. 2022 Jun 20;61(25):e202204052. doi: , 10.1002/anie.202204052. Epub 2022 Apr 25. PMID:35404502^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.