Canfosfamide

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.

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

Mechanism of action

Canfosfamide is specifically activated in the presence of elevated GST P1-1, which is commonly found in various cancer types, including lung cancer, ovarian cancer, and breast cancer. Upon activation, canfosfamide is converted into an alkylating agent that induces DNA damage, leading to apoptosis in cancer cells. This mechanism exploits the increased expression of GST enzymes in tumors, providing a targeted approach to cancer therapy.

Clinical trials

Phase I clinical trials evaluated the safety, tolerability, and pharmacokinetics of canfosfamide. Initial results indicated that canfosfamide was well-tolerated in patients with refractory solid tumors. The primary dose-limiting toxicity observed was myelosuppression.

In Phase II trials, canfosfamide demonstrated clinical activity in various tumor types, especially ovarian cancer and non-small cell lung cancer. The trials revealed partial responses and stable disease in a significant subset of patients. However, adverse effects such as nausea, vomiting, and fatigue were commonly reported.

Phase III trials for canfosfamide have focused on its efficacy as part of combination therapy, particularly with standard chemotherapeutic agents such as cisplatin and gemcitabine. Although early data suggested potential benefits, the trials did not demonstrate significant improvement in overall survival when compared to standard treatments alone. Despite these results, canfosfamide remains an area of active research due to its unique mechanism.

Current status and future directions

Canfosfamide continues to be explored for potential clinical applications, particularly as combination therapy in cancers resistant to conventional treatments. Ongoing research focuses on optimizing dosing regimens and exploring biomarkers that may predict response to treatment. Additionally, studies are investigating canfosfamide in combination with emerging targeted therapies and immunotherapies to enhance its therapeutic efficacy.