Hemiasterlin is a
natural product derived from marine sponges that, like other structurally diverse
peptide-like molecules, binds to the Vinca-
peptide site in
tubulin, disrupts normal microtubule dynamics, and, at stoichiometric amounts, depolymerizes microtubules. Total synthesis of
hemiasterlin and its analogues has been accomplished, and optimal pharmacological features of the series have been explored. The
biological profile of one analogue,
HTI-286, was studied here.
HTI-286 inhibited the polymerization of purified
tubulin, disrupted microtubule organization in cells, and induced mitotic arrest, as well as apoptosis.
HTI-286 was a potent inhibitor of proliferation (mean IC(50) = 2.5 +/- 2.1 nM in 18 human tumor cell lines) and had substantially less interaction with multidrug resistance
protein (
P-glycoprotein) than currently used antimicrotubule agents, including
paclitaxel,
docetaxel,
vinorelbine, or
vinblastine. Resistance to
HTI-286 was not detected in cells overexpressing the
drug transporters
MRP1 or MXR. In athymic mice implanted with human
tumor xenografts,
HTI-286 administered i.v. in saline inhibited the growth of numerous human
tumors derived from
carcinoma of the skin, breast, prostate, brain, and colon. Marked
tumor regression was observed when used on established
tumors that were >1 gram in size. Moreover,
HTI-286 inhibited the growth of human
tumor xenografts (e.g., HCT-15, DLD-1, MX-1W, and KB-8-5) where
paclitaxel and
vincristine were ineffective because of inherent or acquired resistance associated with
P-glycoprotein. Efficacy was also achieved with p.o. administration of
HTI-286. These data suggest that
HTI-286 has excellent preclinical properties that may translate into superior clinical activity, as well as provide a useful synthetic
reagent to probe the
drug contact sites of
peptide-like molecules that interact with
tubulin.