Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin.
The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound seemed 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 (Nature (Lond) 435:519-522, 2005). 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.
Dabydeen
Donnette A
DA
Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick Maryland, USA 21702.
Burnett
James C
JC
Bai
Ruoli
R
Verdier-Pinard
Pascal
P
Hickford
Sarah J H
SJ
Pettit
George R
GR
Blunt
John W
JW
Munro
Murray H G
MH
Gussio
Rick
R
Hamel
Ernest
E
D001665:Binding Sites; D002455:Cell Division; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004988:Ethers, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018942:Macrolides; D008958:Models, Molecular; D015394:Molecular Structure; D014404:Tubulin / Q000378:metabolism*; D000095662:Polyether Polyketides
D004988:Ethers, Cyclic; D005663:Furans; D007659:Ketones; D018942:Macrolides; D014404:Tubulin; C070519:halichondrin B; D000095662:Polyether Polyketides; C490954:eribulin