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Silatecan

Description of silatecan: Silatecan (formerly AR-67) is a synthetic, highly lipophilic derivative of camptothecin, with potential antineoplastic and radiosensitizing activities. Silatecan DB-67 binds to and stabilizes the topoisomerase I-DNA covalent complex, inhibiting the religation of topoisomerase I-mediated single-stranded DNA breaks and producing lethal double-stranded DNA breaks when encountered by the DNA replication machinery; inhibition of DNA replication and apoptosis follow. Camptothecin readily undergoes hydrolysis at physiological pH, changing its conformation from the active lactone structure to an inactive carboxylate form. Modifications on the E ring of camptothecin prevent binding of human serum albumin, which prefers the inactive carboxylate form, thereby enhancing the stability of the active lactone structure and resulting in prolonged agent activity. In addition, this agent may radiosensitize tumor cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:  Arno Therapeutics, Inc.

AR-67(DB-67) is a novel, third-generation camptothecin analogue that has demonstrated high potency in preclinical studies and improved pharmacokinetic properties in humans as compared with first and second-generation products. Arno believes that this unique profile and the potential for oral administration may translate into superior efficacy and patient convenience in the treatment of brain, lung, and other cancers. We believe these advantages could allow DB-67 to become a leading product in the $1.1 billion camptothecin market.

Arno is currently conducting a single agent, ascending dose, Phase I clinical study of DB-67 in patients with advanced solid tumors. The study is evaluating the safety of DB-67, establishing the maximum tolerated dose, and characterizing the plasma PK profile.

 1: Arnold SM, Rinehart JJ, Tsakalozou E, Eckardt JR, Fields SZ, Shelton BJ, DeSimone PA, Kee BK, Moscow JA, Leggas M. A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies. Clin Cancer Res. 2010 Jan 15;16(2):673-80. Epub 2010 Jan 12. PubMed PMID: 20068096; PubMed Central PMCID: PMC2831464.

2: Yeh TK, Li CM, Chen CP, Chuu JJ, Huang CL, Wang HS, Shen CC, Lee TY, Chang CY, Chang CM, Chao YS, Lin CT, Chang JY, Chen CT. Antitumor activities and pharmacokinetics of silatecans DB-67 and DB-91. Pharmacol Res. 2010 Feb;61(2):108-15. Epub 2009 Jul 28. PubMed PMID: 19643180.

3: Sivak WN, Zhang J, Petoud S, Beckman EJ. Incorporation of ionic ligands accelerates drug release from LDI-glycerol polyurethanes. Acta Biomater. 2010 Jan;6(1):144-53. Epub 2009 Jun 11. PubMed PMID: 19524075.

4: Sivak WN, Zhang J, Petoud S, Beckman EJ. Simultaneous drug release at different rates from biodegradable polyurethane foams. Acta Biomater. 2009 Sep;5(7):2398-408. Epub 2009 Apr 1. PubMed PMID: 19398389.

5: Kruszewski S, Ziomkowska B, Cyrankiewicz M, Wybranowski T. The comparison of biophysical properties of DB-67 and its ester DB-67-4ABTFA determined by fluorescence spectroscopy methods. Biosystems. 2008 Dec;94(3):270-5. Epub 2008 Jul 31. PubMed PMID: 18718502.

6: Joguparthi V, Anderson BD. Effect of cyclodextrin complexation on the liposome permeability of a model hydrophobic weak Acid. Pharm Res. 2008 Nov;25(11):2505-15. Epub 2008 Jul 19. PubMed PMID: 18642063.

7: Sivak WN, Pollack IF, Petoud S, Zamboni WC, Zhang J, Beckman EJ. LDI-glycerol polyurethane implants exhibit controlled release of DB-67 and anti-tumor activity in vitro against malignant gliomas. Acta Biomater. 2008 Jul;4(4):852-62. Epub 2007 Nov 17. PubMed PMID: 18440882.

8: Zamboni WC, Jung LL, Strychor S, Joseph E, Zamboni BA, Fetterman SA, Sidone BJ, Burke TG, Curran DP, Eiseman JL. Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice. Invest New Drugs. 2008 Oct;26(5):399-406. Epub 2008 Feb 2. PubMed PMID: 18246299.

9: Joguparthi V, Feng S, Anderson BD. Determination of intraliposomal pH and its effect on membrane partitioning and passive loading of a hydrophobic camptothecin, DB-67. Int J Pharm. 2008 Mar 20;352(1-2):17-28. Epub 2007 Oct 12. PubMed PMID: 18065174; PubMed Central PMCID: PMC2277365.

10: Joguparthi V, Xiang TX, Anderson BD. Liposome transport of hydrophobic drugs: gel phase lipid bilayer permeability and partitioning of the lactone form of a hydrophobic camptothecin, DB-67. J Pharm Sci. 2008 Jan;97(1):400-20. PubMed PMID: 17879989.

11: Xiang TX, Jiang ZQ, Song L, Anderson BD. Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Mol Pharm. 2006 Sep-Oct;3(5):589-600. PubMed PMID: 17009858.

12: Horn J, Jordan SL, Song L, Roberts MJ, Anderson BD, Leggas M. Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Nov 21;844(1):15-22. Epub 2006 Jul 21. PubMed PMID: 16860004.

13: Chen AY, Shih SJ, Garriques LN, Rothenberg ML, Hsiao M, Curran DP. Silatecan DB-67 is a novel DNA topoisomerase I-targeted radiation sensitizer. Mol Cancer Ther. 2005 Feb;4(2):317-24. PubMed PMID: 15713902.

14: Lopez-Barcons LA, Zhang J, Siriwitayawan G, Burke TG, Perez-Soler R. The novel highly lipophilic topoisomerase I inhibitor DB67 is effective in the treatment of liver metastases of murine CT-26 colon carcinoma. Neoplasia. 2004 Sep-Oct;6(5):457-67. PubMed PMID: 15548354; PubMed Central PMCID: PMC1531650.

15: Bence AK, Mattingly CA, Burke TG, Adams VR. The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells. Cancer Chemother Pharmacol. 2004 Oct;54(4):354-60. Epub 2004 Jun 12. PubMed PMID: 15197485.

16: Lansiaux A, Bailly C. [A symphony for the camptothecins]. Bull Cancer. 2003 Mar;90(3):239-45. French. PubMed PMID: 12801826.

17: Du W, Kaskar B, Blumbergs P, Subramanian PK, Curran DP. Semisynthesis of DB-67 and other silatecans from camptothecin by thiol-promoted addition of silyl radicals. Bioorg Med Chem. 2003 Feb 6;11(3):451-8. PubMed PMID: 12517440.

18: Xiang TX, Anderson BD. Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified beta-cyclodextrin. Pharm Res. 2002 Aug;19(8):1215-22. PubMed PMID: 12240949.

19: Bom D, Curran DP, Zhang J, Zimmer SG, Bevins R, Kruszewski S, Howe JN, Bingcang A, Latus LJ, Burke TG. The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity. J Control Release. 2001 Jul 6;74(1-3):325-33. PubMed PMID: 11489514.

20: Bom D, Curran DP, Kruszewski S, Zimmer SG, Thompson Strode J, Kohlhagen G, Du W, Chavan AJ, Fraley KA, Bingcang AL, Latus LJ, Pommier Y, Burke TG. The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem. 2000 Oct 19;43(21):3970-80. PubMed PMID: 11052802.