Vosaroxin: A Novel Anticancer Agent

Vosaroxin is a first-in-class anticancer quinolone derivative, or AQD, a class of compounds that has not been used previously for the treatment of cancer. Vosaroxin exerts potent anticancer activity through a mechanism that involves intercalation into DNA and an inhibition of topoisomerase II activity that results in replication-dependent, site-selective double-strand breaks in DNA. The DNA damage induced by vosaroxin is analogous to that of the quinolone antibiotics in bacterial cells.¹

Topoisomerase II enzymes are essential for the survival of eukaryotic cells. By cleaving and then re-ligating double-strand breaks, they maintain DNA topology during replication and support chromosome condensation, decondensation, and segregation.^2,3

Vosaroxin blocks the re-ligation of topoisomerase II-induced double-strand breaks at selective sites in DNA. This leads to G2 arrest and cell death by apoptosis.^1,4

Vosaroxin is differentiated chemically and mechanistically from other clinically active topoisomerase II inhibitors. It is not a P-glycoprotein (P-gp) substrate, thereby evading the most common mechanism for multidrug resistance. This may contribute to the vosaroxin activity observed in anthracycline-resistant patients.^5,6 Other important attributes that differentiate vosaroxin from existing therapies are its targeted DNA damage, p53 family independence, limited distribution to normal tissues relative to anthracyclines, and a more chemically stable molecular structure.^7-10 These attributes may contribute to vosaroxin's broad therapeutic profile in patients with various tumor types.

The mechanism of action of vosaroxin contrasts with the more promiscuously intercalative tetracyclic core of the anthracyclines, and this may lead to an improved toxicity profile. In addition, anthracyclines are also associated with significant production of reactive oxygen species (ROS), which have been linked to cardiotoxicity.¹¹ By comparison, the vosaroxin naphthyridine core is less chemically reactive and produces few ROS, potentially reducing the risk of cardiotoxicity.¹⁰

Favorable profile compared with known topoisomerase II inhibitors

Active anthracycline-resistant settings
Evades the most common mechanism (P-gp) for multidrug resistance
Low potential for drug-drug interactions

p53 family-independent activity
Limited distribution to normal tissues relative to anthracyclines
Lower potential for cardio/organ toxicity

	Vosaroxin	Doxorubicin	Daunorubicin	Etoposide
Drug Class	Quinolone Derivative	Anthracycline	Anthracycline	Epipodophyllotoxin
Common Clinical application	Under clinical investigation in AML and ovarian cancer	Broadly used in solid and hematologic tumors	Leukemias	SCLC, NSCLC, ovarian cancer, lymphomas
Primary mechanism of action	DNA intercalator, topoisomerase II poison and inhibitor causing site-selective DNA damage	DNA intercalator, topoisomerase II poison and inhibitor	DNA intercalator, topoisomerase II poison and inhibitor	Topoisomerase II poison
DNA damage	Site-selective double-strand breaks	Promiscuous single- and double-strand breaks	Promiscuous single- and double-strand breaks	Promiscuous single- and double-strand breaks
p53 influence	No	Mixed	Mixed	Yes
p-glycopritein	No	Yes	Yes	Yes

Vosaroxin poisons topoisomerase II

DNA intercalation and poisoning of topoisomerase II prevents repair of topoisomerase II-induced site-selective DNA double-strand breaks.

Vosaroxin inhibits topoisomerase II

Reduced DNA damage at higher drug concentrations indicates inhibition of topoisomerase II-induced DNA cleavage, which is necessary to maintain normal DNA topology.

Vosaroxin stalls the replication fork

Vosaroxin-induced DNA damage causes the replication fork to stall as it encounters the drug-bound DNA/topoisomerase II complex.

Vosaroxin activity leads to G2 arrest and apoptosis

The accumulation of DNA damage and replication stress trigger programmed cell death (apoptosis).

1. Stockett D, Byl JA, Hawtin RE, et al. SNS-595 is a potent anti-tumor agent that has a dual mechanism of action: DNA intercalation and site-selective topoisomerase II poisoning. In: Proceedings of the 99th Annual Meeting of the American Association for Cancer Research. San Diego, CA: American Association for Cancer Research; 2008. Abstract 1860. 2. Wang JC. DNA topoisomerases. Annu Rev Biochem. 1985;54:665-697. 3. Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70:369-413. 4. Hawtin RE, Stockett D, Kimmel RA, et al. Sensitivity to SNS-595 is related to activation of double strand DNA break repair pathways including homologous recombination. In: Proceedings of the 99th Annual Meeting of the American Association for Cancer Research. San Diego, CA: American Association for Cancer Research; 2008. Abstract 337. 5. McGuire WP, Hirte HW, Matulonis UA, et al. A phase II trial of SNS-595 in women with platinum resistant epithelial ovarian cancer. J Clin Oncol. 2008; 26(suppl): Abstract 5582. 6. Lancet J, Kantarjian H, Ravandi F, et al. SNS-595 demonstrates clinical responses in a phase I study in acute leukemia. Blood. 2007;110:442. 7. Creasey WA, McIntosh LS, Brescia T, et al. Clinical effects and pharmacokinetics of different dosage schedules of adriamycin. Cancer Res. 1976;36:216-221. 8. Greene W, Huffman D, Wiernik PH, Schimpff S, Benjamin R, Bachur N. High-dose daunorubicin therapy for acute nonlymphocytic leukemia: correlation of response and toxicity with pharmacokinetics and intracellular daunorubicin reductase activity. Cancer. 1972;30:1419-1427. 9. Hoch U, Silverman JA. SNS-595 demonstrates predictable, dose-proportional pharmacokinetics in three Phase 1 clinical studies. Paper presented at: 2007 American Association of Pharmaceutical Scientists Annual Meeting and Exposition; November 11-15, 2007; San Diego, CA. Abstract W4491. 10. Data on file. Sunesis Pharmaceuticals, Inc.; 2008. 11. Gewirtz D. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57:727-741. 12. Hawtin RE, Arkin MR, Fox JA. Ex vivo activity of SNS-595 against biopsies of acute myeloid leukemia, triple negative breast and ovarian cancers supports ongoing and potential clinical indications. In: Proceedings of the 99th Annual Meeting of the American Association for Cancer Research. San Diego, CA: American Association for Cancer Research; 2008. Abstract 2830.

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Sunesis is developing vosaroxin in both AML and ovarian cancer.