1.A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors.
Rocha-Lima CM1, Bayraktar S, Macintyre J, Raez L, Flores AM, Ferrell A, Rubin EH, Poplin EA, Tan AR, Lucarelli A, Zojwalla N. Cancer. 2012 Sep 1;118(17):4262-70. doi: 10.1002/cncr.27428. Epub 2012 Jan 31.
BACKGROUND: E7974, a synthetic analog of hemiasterlin, interacts with the tubulin molecule and overcomes resistance to other antitubulin drugs (taxanes and vinca alkaloids).
2.Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin.
Kuznetsov G1, TenDyke K, Towle MJ, Cheng H, Liu J, Marsh JP, Schiller SE, Spyvee MR, Yang H, Seletsky BM, Shaffer CJ, Marceau V, Yao Y, Suh EM, Campagna S, Fang FG, Kowalczyk JJ, Littlefield BA. Mol Cancer Ther. 2009 Oct;8(10):2852-60. doi: 10.1158/1535-7163.MCT-09-0301.
E7974 is a synthetic analogue of the marine sponge natural product hemiasterlin. Here, we show that E7974, such as parental hemiasterlin, acts via a tubulin-based antimitotic mechanism. E7974 inhibits polymerization of purified tubulin in vitro with IC(50) values similar to those of vinblastine. In cultured human cancer cells, E7974 induces G(2)-M arrest and marked disruption of mitotic spindle formation characteristic of tubulin-targeted anticancer drugs. Extensive hypodiploid cell populations are seen in E7974-treated cells, indicating initiation of apoptosis after prolonged G(2)-M blockage. Consistent with this observation, E7974 induces caspase-3 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis. Only a short cellular exposure to E7974 is sufficient to induce maximum mitotic arrest, suggesting that E7974's antitumor effects in vivo may persist even after blood levels of the drug decrease after drug administration.