Work done on synthesizing halicondrin B (NSC 609395) showed that only a portion of the molecule was needed for potent biological activity. The selected analog is a novel chemotype of tubulin disruptors and shows potent invitro and in vivo activty.
IC50 of 6.9 micromolar for rate inhibition and 6.0 micromolar for extent inhibition. Inhibits competitively inhibits binding of vinblastine (Ki 0.88 micromolar) and dolostatin 10 (Ki 5.9 micromolar) to tubulin.
i.v. dose of 1.5 mg/kg in rats showed extensive distribution with levels remaining at 20-30 ng/mL for 10 hours. After oral dose of 2.5 mg/kg, plasma levels were only 6-7 nM for less than 6 hours. Pretreatment with 25 mg/kg of cyclosporine before the oral dose gave plasma levels of 12 nM for 4-8 hours.
The compound produced bone marrow toxicity in both rats and dogs. Given once day on days 1, 5, and 9, the compound produced reversible myelotoxicity at doses of 0.8 mg/m^2/day in dogs and 1.2 mg/m^2/day in rats. At higher doses, gastrointestinal toxicity occurred in dogs and hepatic toxicity was present in rats. In vitro bone marrow assays did not demonstrate significant species differences between human, dog, and mouse CFU-GM cell sensitivity to the compound.
Using an intermittent i.v. treatment regimen (Q4D x 3) and doses from 0.75 mg/kg to 1.5 mg/kg, there were 14/15 complete tumor regressions in the MDA-MB-435 melanoma line and 14/15 tumor free animals in the NCI-H522 lung model with minimal to no toxicity. For MDA-MB-435, remissions ranged from 24 to 41 days. For NCI-H522, 14/15 animals showed tumor-free status (no tumor regrowth for at least 37 days after treatment).
Screening data summary reports for individual experiments using the DTP invivo solid tumor and/or toxicity testing models are available below. Comments are based upon the results of individual experiments. Variations in outcome can result from changes in many experimental variables including the drug doses, administration routes, dosing schedules, drug vehicles, tumor models and tumor passage status.