MedKoo product information:

 EC-0489

EC0489  is a folate receptor-targeting cytotoxic drug conjugate consisting of a folate vitamin analogue linked to a vinca alkaloid microtubule destabilizing agent with potential antineoplastic activity. Mediated through its folate moiety, folate receptor-targeted Vinca alkaloid EC0489 delivers the cytotoxic vinca alkaloid moiety directly to cells expressing folic acid receptors, frequently upregulated in many types of tumor cells. After ligand-receptor internalization, the vinca alkaloid moiety binds to tubulin and disrupts microtubule assembly-disassembly dynamics, resulting in cell cycle arrest and apoptosis. The relative tumor cell specificity of this agent reduces the toxicity profile of its Vinca alkaloid moiety. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

During a phase I trial of EC145 (a folate-targeted vinca alkaloid conjugate), constipation was identified as the dose-limiting toxicity, probably from a nonfolate receptor-related liver clearance process capable of releasing unconjugated vinca alkaloid from EC145 and shuttling it to the bile. Here, we report on the selective placement of novel carbohydrate segments (1-amino-1-deoxy-glucitolyl-γ-glutamate) spaced in-between the folate and vinca alkaloid moieties of EC145, which yielded a new agent (EC0489) that is equipotent but less toxic than EC145. Whereas both compounds could cure tumor-bearing mice reproducibly, EC0489 differed from EC145 with i) a shorter elimination half-life, ii) approximately 70% decrease in bile clearance, iii) a 4-fold increase in urinary excretion, and iv) improved tolerability in rodents. This combination of improvements justified the clinical evaluation of EC0489 where currently administered dose levels have exceeded the maximal tolerated dose of EC145 by approximately 70%, thereby reflecting the translational benefits to this new approach. (source: J Pharmacol Exp Ther. 2011 Feb;336(2):336-43. Epub 2010 Oct 26.).

Current developer:    Endocyte Inc.

 1: Leamon CP, Reddy JA, Klein PJ, Vlahov IR, Dorton R, Bloomfield A, Nelson M, Westrick E, Parker N, Bruna K, Vetzel M, Gehrke M, Nicoson JS, Messmann RA, LoRusso PM, Sausville EA. Reducing undesirable hepatic clearance of a tumor-targeted vinca alkaloid via novel saccharopeptidic modifications. J Pharmacol Exp Ther. 2011 Feb;336(2):336-43. Epub 2010 Oct 26. PubMed PMID: 20978169.