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E7974

E7974 is an analog of the sponge-derived anti-microtubule tripeptide hemiasterlin with antimitotic and potential antineoplastic activities. Hemiasterlin analog E7974 binds to the Vinca domain on tubulin, resulting in inhibition of tubulin polymerization and microtubule assembly; depolymerization of exsiting microtubules; inhibition of mitosis; and inhibition of cellular proliferation. This agent may have more affinity for the beta-3 tubulin isotype. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

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. Interactions of E7974 with purified tubulin were investigated using two synthetic tritiated photoaffinity analogues incorporating a benzophenone photoaffinity moiety at two different positions of the E7974 scaffold. Both analogues preferentially photolabeled alpha-tubulin, although minor binding to beta-tubulin was also detected. E7974 thus seems to share a unique, predominantly alpha-tubulin-targeted mechanism with other hemiasterlin-based compounds, suggesting that, unlike many tubulin-targeted natural products and related drugs, the hemiasterlins evolved to mainly target alpha-tubulin, not beta-tubulin subunits. see http://www.ncbi.nlm.nih.gov/pubmed/19825803.

Current developer:  Eisai Inc.

1: Meir A, Rubinsky B. Distributed network, wireless and cloud computing enabled 3-D ultrasound; a new medical technology paradigm. PLoS One. 2009 Nov 19;4(11):e7974. PubMed PMID: 19936236; PubMed Central PMCID: PMC2775631.

2: Kuznetsov G, 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. Tubulin-based antimitotic mechanism of E7974, a novel analogue of the marine sponge natural product hemiasterlin. Mol Cancer Ther. 2009 Oct;8(10):2852-60. PubMed PMID: 19825803.