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Received for publication May 22, 2006.
Revised August 3, 2006.
Accepted for publication August 29, 2006.
The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analogue, which has been selected for clinical trials in human patients. Invariably NSC 707389 was more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on 
-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound appeared to induce an aberrant tubulin assembly reaction, as occurs with vinblastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared binding site on tubulin consistent with their biochemical properties. Of the two tubulin structures available, we selected for modeling the complex of a stathmin fragment with two tubulin heterodimers with two bound colchicinoid molecules and a single bound vinblastine between the two heterodimers (Gigant et al., 2005, Nature 435:519-522). Halichondrin B and NSC 707389 fit snugly between the two heterodimers adjacent to the exchangeable site nucleotide. Fitting the compounds into this site, which was also close to the vinblastine site, resulted in enough movement of amino acid residues at the vinblastine site to cause the latter compound to bind less well to tubulin. The model suggests that halichondrin B and NSC 707389 most likely form highly unstable, small aberrant tubulin polymers rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides.
Key words:
Structure-activity relationships and modeling, Structure/function/mechanism, Cytoskeletal targets
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