Synthesis and Biological Activity of Analogues of the Antimicrotubule AgentN,β,β-Trimethyl-l-phenylalanyl-N-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N¹,3-dimethyl-l-valinamide (HTI-286)

Abstract

Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.

Intravesical combination treatment with antisense oligonucleotides targeting heat shock protein-27 and HTI-286 as a novel strategy for high-grade bladder cancer

“…HTI-286, a fully synthetic analogue of the natural tripeptide hemiasterlin, interferes with spindle-microtubule dynamics leading to concentration-dependent apoptosis [12][13][14][15][16][17]. This chemotherapeutic has potent cytotoxic properties and may be useful in the setting of chemoresistance because it is a poor substrate for the efflux pump P-glycoprotein (18).…”

“…One of these is HTI-286, a fully synthetic analogue of the natural tripeptide hemiasterlin, which binds to the tubulin heterodimer at a unique site and interferes with spindle-microtubule dynamics at very low concentrations (12)(13)(14)(15)(16)(17). HTI-286 is advantageous when compared with taxanes or conventional chemotherapeutic agents against bladder cancer including mitomycin C, because it is a poor substrate for P-glycoprotein (MDR1) and thus reduces the possibility of multidrug resistance (18).…”

Intravesical Chemotherapy of High-Grade Bladder Cancer with HTI-286, A Synthetic Analogue of the Marine Sponge Product Hemiasterlin

“…Experimental compounds in clinical trials include novel taxanes, epothilones, and peptide-like agents. HTI-286 is a fully synthetic analogue of the naturally occurring tripeptide hemiasterlin (10,11). HTI-286 binds to the tubulin heterodimer at a unique site that seems to be in the interface of the tubulin subunits and is close to but distinct from the Vinca binding site (12,13).…”

Mapping the bound conformation and protein interactions of microtubule destabilizing peptides by STD–NMR spectroscopy

“…However, these same studies demonstrate that the aromatic group of I can tolerate significant structural changes while retaining good inhibition of tubulin polymerization, and that larger groups at H14/15 and H4/5 lead to less potent analogs. 5,7 Indeed, SAR studies show that the H4/5 gem-dimethyl is a key component necessary for potent activity. This does not correlate with the 1 s STD results.…”

“…The SAR, however, shows the role of the olefin to be more important for conformational rigidity than for close contact of its substituents. 7 The discrepancies described above prompted us to examine the STD results more closely. At 1 s irradiation time, the extent of STD transfer was highly dependent on the type of proton in the molecule (see Table 1), that is, the extent of saturation transfer occurs in the following order: aromatic protons > alpha protons > non-coupled methyl groups > coupled methyl groups.…”