BMS-188797

Microtubules are highly dynamic polymers of α/β‐tubulin that represent major components of the cytoskeleton and have been established as an attractive druggable target of tumors. Taxol, also known as Paclitaxel, is a microtubule‐stabilizing agent that binds stoichiometrically to a specific site in β‐tubulin, where is out of but nearby the interacting interface of α/β‐tubulin complex, to improve the complex stability through an allosterically regulatory mechanism. In this study, the systematic binding profile of taxol and its 22 structurally diverse, medicinally relevant analogues (termed as taxalogues) to the specific site of β‐tubulin as well as their effects on the α/β‐tubulin complex stability were created and investigated by using structural modeling, dynamics simulation, and energetics analysis. Two helices H1 and H2 of β‐tubulin were identified as key hotspots at the α/β‐tubulin interface to mediate the binding event of β‐tubulin to α‐tubulin. Taxalogue binding can trigger a conformational displacement in the H1 and H2 to elicit the stabilization (or destabilization) of α/β‐tubulin. However, strong taxalogue binding potency to β‐tubulin does not mean effective α/β‐tubulin stabilization; there is only an indirect, moderate correlation between them. Cell viability assay revealed that the taxalogue‐induced α/β‐tubulin stabilization, but not the taxalogue binding, directly influences the antitumor activity of taxalogues. The activity increases in the order: SB‐T‐1214 < docetaxel < taxol < larotaxel < cisplatin < cabazitaxel.