Canfosfamide

Canfosfamide
Clinical data
Other names	TLK286
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name (2S)-2-Amino-5-[[(2R)-3-[2-[bis[bis(2-chloroethyl)amino]phosphoryloxy]ethylsulfonyl]-1-[[(R)-carboxy(phenyl)methyl]amino]-1-oxopropan-2-yl]amino]-5-oxopentanoic acid;
CAS Number	158382-37-7 ; HCl: 439943-59-6;
PubChem CID	5312109;
DrugBank	DB04972;
ChemSpider	4471543;
UNII	1RS284BFUI;
ChEBI	CHEBI:135883;
ChEMBL	ChEMBL2111086;
CompTox Dashboard (EPA)	DTXSID40166412 ;
Chemical and physical data
Formula	C26H40Cl4N5O10PS
Molar mass	787.46 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1=CC=C(C=C1)[C@H](C(=O)O)NC(=O)[C@H](CS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)NC(=O)CC[C@@H](C(=O)O)N;
	InChI InChI=1S/C26H40Cl4N5O10PS/c27-8-12-34(13-9-28)46(42,35(14-10-29)15-11-30)45-16-17-47(43,44)18-21(32-22(36)7-6-20(31)25(38)39)24(37)33-23(26(40)41)19-4-2-1-3-5-19/h1-5,20-21,23H,6-18,31H2,(H,32,36)(H,33,37)(H,38,39)(H,40,41)/t20-,21-,23+/m0/s1; Key:OJLHWPALWODJPQ-QNWVGRARSA-N;

Canfosfamide (development code TLK286) an investigational anticancer drug that has been evaluated for its potential efficacy in treating a variety of solid tumors. TLK286 functions as a prodrug activated by the enzyme glutathione S-transferase P1-1 (GST P1-1), which is often overexpressed in cancer cells, leading to selective cytotoxicity towards tumor cells compared to normal cells.^[1]^[2]^[3]^[4]

Mechanism of action

Canfosfamide is specifically activated in the presence of elevated GST P1-1, which is commonly found in various cancer types. Upon activation, it is converted into an alkylating agent that induces DNA damage, leading to apoptosis in cancer cells.^[1]^[2]^[3]^[5]^[6]

Clinical trials

Phase I clinical trials evaluated the safety, tolerability, and pharmacokinetics of canfosfamide.^[1] Phase II trials evaluated clinical activity in various tumor types, especially ovarian cancer and non-small cell lung cancer.^[7] Phase III trials focused on its efficacy as part of combination therapy, particularly with standard chemotherapeutic agents. However, the trials did not demonstrate significant improvement in overall survival when compared to standard treatments alone.^[3]

References

^ ^a ^b ^c Rosen LS, Brown J, Laxa B, Boulos L, Reiswig L, Henner WD, Lum RT, Schow SR, Maack CA, Keck JG, Mascavage JC, Dombroski JA, Gomez RF, Brown GL (May 2003). "Phase I study of TLK286 (glutathione S-transferase P1-1 activated glutathione analogue) in advanced refractory solid malignancies". Clinical Cancer Research. 9 (5): 1628–38. PMID 12738715.
^ ^a ^b Tew KD (August 2005). "TLK-286: a novel glutathione S-transferase-activated prodrug". Expert Opinion on Investigational Drugs. 14 (8): 1047–54. doi:10.1517/13543784.14.8.1047. PMID 16050796.
^ ^a ^b ^c Vergote I, Finkler N, del Campo J, Lohr A, Hunter J, Matei D, Kavanagh J, Vermorken JB, Meng L, Jones M, Brown G, Kaye S (September 2009). "Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer". European Journal of Cancer. 45 (13). Oxford, England: 2324–32. doi:10.1016/j.ejca.2009.05.016. PMID 19515553.
^ >"Canfosfamide". AdisInsight. Springer Nature Switzerland AG.
^ Montero AJ, Jassem J (July 2011). "Cellular redox pathways as a therapeutic target in the treatment of cancer". Drugs. 71 (11): 1385–96. doi:10.2165/11592590-000000000-00000. PMID 21812504.
^ Brüning A, Mylonas I (May 2011). "New emerging drugs targeting the genomic integrity and replication machinery in ovarian cancer". Archives of Gynecology and Obstetrics. 283 (5): 1087–96. doi:10.1007/s00404-010-1757-x. PMID 21082186.
^ Kavanagh JJ, Gershenson DM, Choi H, Lewis L, Patel K, Brown GL, Garcia A, Spriggs DR (2005). "Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer". International Journal of Gynecological Cancer. 15 (4): 593–600. doi:10.1111/j.1525-1438.2005.00114.x. PMID 16014111.

[Rosen_2003-1] Rosen LS, Brown J, Laxa B, Boulos L, Reiswig L, Henner WD, Lum RT, Schow SR, Maack CA, Keck JG, Mascavage JC, Dombroski JA, Gomez RF, Brown GL (May 2003). "Phase I study of TLK286 (glutathione S-transferase P1-1 activated glutathione analogue) in advanced refractory solid malignancies". Clinical Cancer Research. 9 (5): 1628–38. PMID 12738715.

[Tew_2005-2] Tew KD (August 2005). "TLK-286: a novel glutathione S-transferase-activated prodrug". Expert Opinion on Investigational Drugs. 14 (8): 1047–54. doi:10.1517/13543784.14.8.1047. PMID 16050796.

[Vergote_2009-3] Vergote I, Finkler N, del Campo J, Lohr A, Hunter J, Matei D, Kavanagh J, Vermorken JB, Meng L, Jones M, Brown G, Kaye S (September 2009). "Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer". European Journal of Cancer. 45 (13). Oxford, England: 2324–32. doi:10.1016/j.ejca.2009.05.016. PMID 19515553.

[4] >"Canfosfamide". AdisInsight. Springer Nature Switzerland AG.

[Montero_2011-5] Montero AJ, Jassem J (July 2011). "Cellular redox pathways as a therapeutic target in the treatment of cancer". Drugs. 71 (11): 1385–96. doi:10.2165/11592590-000000000-00000. PMID 21812504.

[Brüning_2011-6] Brüning A, Mylonas I (May 2011). "New emerging drugs targeting the genomic integrity and replication machinery in ovarian cancer". Archives of Gynecology and Obstetrics. 283 (5): 1087–96. doi:10.1007/s00404-010-1757-x. PMID 21082186.

[Kavanagh_2005-7] Kavanagh JJ, Gershenson DM, Choi H, Lewis L, Patel K, Brown GL, Garcia A, Spriggs DR (2005). "Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer". International Journal of Gynecological Cancer. 15 (4): 593–600. doi:10.1111/j.1525-1438.2005.00114.x. PMID 16014111.

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