Halichondrin B and its analog, E7389.

Halichondrin B (NSC 609395)
E7389 (NSC 707389)

1986 Halichondrin B (NSC 609395) is a macrocyclic polyether initially isolated from the sponge Halichondria okadai received in 1986.

1992 It was accepted for preclinical development by NCI in 1992 after it was found to be highly cytotoxic in murine leukemia cells. Difficulty in collecting sufficient material for developmental studies slowed the progress of this interesting material.

1998 The drug received a new lease on life with the development of a complete synthetic method in 1998 by Dr. Yoshito Kishi of Harvard University and the discovery that its activity resides in the macrocyclic lactone C1-C38 moiety.¹ The way was now open for development of a simplified synthetic analog. Researchers at Eisai Research Institute, who licensed the synthetic technology from Harvard, accomplished the synthesis of the resulting drug, E7389 (NSC 707389). E7389 was presented to the DDG for preclinical development in 1998.

E7389, like its parent natural compound, is classified as a tubulin depolymerizer, and it shows activity at least equal to the naturally occurring chemical. It acts to disrupt the polymerization of the microtubules necessary in mitosis.² This general characteristic places E7389 in the group of drugs that includes Vinca alkaloids, dolastatins, cryptophycin, and so forth, but its tubulin interactions appear to be unique, and it was found to have greater activity against lung and breast tumors in animal studies than either the parent halichondrin B or paclitaxel.³

2002 E7389 entered phase I clinical trials in 2002 and has recently progressed to phase II clinical trials for the treatment of advanced and metastatic breast cancer. The trials are taking place across the United States under the sponsorship of Eisai.⁴

¹ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsk BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 2001;61:1013–1021.

² Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem 1991;266:15882–15889.

³ Fang FG. Synthetic studies on the halichondrin b analog, E7389. Abstract presented at Frontiers in Chemistry and Medicine I, 11 November 2004.

⁴ ClinicalTrials.gov.

⁵ Interview with Dr. David Newman. Palladian Partners. April 2005.

Link:

Halichondrin B poster (pdf)

More than 1,100 vials of Halichondrin B were distributed during 2004 for phase I and II clinical trials.

“DTP’s repository houses some 170,000 extracts from samples of more than 70,000 plant and 10,000 marine organisms collected from more than 25 countries, as well as more than 30,000 extracts of diverse bacteria and fungi. So far, some 4,000 natural-source extracts have shown in vitro activity against human cancer cells, making them worthy of further study by DTP researchers looking to find nature’s next blockbuster drug.”⁵

—David Newman, Ph.D., Natural Products Branch, NCI