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

Reddy, Joseph and Nelson, Melissa and Dircksen, Christina and Vetzel, Marilynn and Johnson, Theresa and Cross, Vicky and Westrick, Elaine and Qi, LongWu and Hahn, Spencer and Santhapuram, Hari Krishna and Parham, Garth and Wang, Kevin and Vaughn, Jeremy F and Pugh, Michael and Lu, June and Klein, Pat and Vlahov, Iontcho and Leamon, Christopher (2020) Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent. Scientific reports, 10 (1). ISSN 20452322

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.

Item Type: Article
Date Deposited: 01 Sep 2020 00:45
Last Modified: 01 Sep 2020 00:45
URI: https://oak.novartis.com/id/eprint/41901

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