Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent.

Abstract

Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

• Authors: Joseph A Reddy, Melissa Nelson, Christina Dircksen, Marilynn Vetzel, Theresa Johnson, Vicky Cross, Elaine Westrick, LongWu Qi, Spencer Hahn, Hari Krishna Santhapuram, Garth Parham, Kevin Wang, Jeremy F Vaughn, Albert Felten, Michael Pugh, June Lu, Patrick Klein, Iontcho R Vlahov, Christopher P Leamon
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 12772 (07 29 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32728172 (Publication Type: Journal Article)

Chemical References

• Alkylating Agents
• Antineoplastic Agents
• Cross-Linking Reagents
• EC145
• Folate Receptors, GPI-Anchored
• Ligands
• Vinca Alkaloids
• DNA
• Folic Acid
• Paclitaxel
• Cisplatin

Topics

• Alkylating Agents (chemistry)
• Animals
• Antineoplastic Agents (pharmacology)
• Cattle
• Cisplatin (administration & dosage)
• Cross-Linking Reagents (pharmacology)
• DNA (chemistry)
• Dogs
• Drug Delivery Systems
• Drug Design
• Drug Evaluation, Preclinical
• Endometrial Neoplasms (drug therapy)
• Female
• Folate Receptors, GPI-Anchored (chemistry)
• Folic Acid (analogs & derivatives, pharmacology)
• Humans
• Inhibitory Concentration 50
• KB Cells
• Ligands
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Ovarian Neoplasms (drug therapy)
• Paclitaxel (administration & dosage)
• Rats
• Triple Negative Breast Neoplasms (drug therapy)
• Vinca Alkaloids (pharmacology)
• Xenograft Model Antitumor Assays