Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen PSI, Switzerland.
Computational & Chemical Biology, Istituto Italiano di Tecnologia, via Morego 30, 16163, Genova, Italy.
Angew Chem Int Ed Engl. 2022 Jun 20;61(25):e202204052. doi: 10.1002/anie.202204052. Epub 2022 Apr 25.
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 α-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.
在这项研究中，我们利用之前进行的晶体学片段筛选，仅通过两轮直接的化学合成，开发出了抗微管蛋白小分子 Todalam。Todalam 结合到一个新的微管蛋白结合位点，破坏细胞中的微管网络，将细胞阻滞在 G2/M 期，诱导细胞死亡，并与长春花碱协同作用。该化合物通过充当分子塞来破坏微管，该分子塞从空间上抑制α-微管蛋白亚基的弯曲到直的构象转换，并且通过将微管二聚体隔离成组装无能力的寡聚物。我们的结果首次描述了从片段中生成完全合理设计的微管蛋白抑制剂，该抑制剂显示出独特的作用机制。因此，它们证明了微管结合片段作为创新的抗微管蛋白药物和化学探针发现活动有价值的起点的有用性。
