Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners

(+)-Discodermolide is a microtubule-stabilizing
agent with potential
for the treatment of taxol-refractory malignancies. (+)-Discodermolide
congeners containing the C-3′-phenyl side chain of taxol (paclitaxel)
were synthesized based on computational docking models predicting
this moiety would fill an aromatic pocket of β-tubulin insufficiently
occupied by (+)-discodermolide, thereby conferring improved ligand–target
interaction. It was recently demonstrated, however, that the C-3′-phenyl
side chain occupied a different space, instead extending toward the
M-loop of β-tubulin, where it induced a helical conformation,
hypothesized to improve lateral contacts between adjacent microtubule
protofilaments. This insight led us to evaluate the biological activity
of hybrid congeners using a panel of genetically diverse cancer cell
lines. Hybrid molecules retained the same tubulin-polymerizing profile
as (+)-discodermolide. Since (+)-discodermolide is a potent inducer
of accelerated senescence, a fate that contributes to drug resistance,
congeners were also screened for senescence induction. Flow cytometric
and transcriptional analysis revealed that the hybrids largely retained
the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive
cell models, the congeners had improved dose-response parameters relative
to (+)-discodermolide and, in some cases, were superior to taxol.
However, in cells susceptible to senescence, EMax increased without concomitant improvements in EC50 such that overall dose-response profiles resembled that of (+)-discodermolide.