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Reddy, Joseph A.; Nelson, Melissa; Dircksen, Christina; Vetzel, Marilynn; Johnson, Theresa; Cross, Vicky; Westrick, Elaine; Qi, LongWu; Hahn, Spencer; Santhapuram, Hari Krishna; Parham, Garth; Wang, Kevin; Vaughn, Jeremy F.; Felten, Albert; Pugh, Michael; Lu, June; Klein, Patrick; Vlahov, Iontcho R.; Leamon, Christopher P.

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

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  • Media type: E-Article
  • Title: Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
  • Contributor: Reddy, Joseph A.; Nelson, Melissa; Dircksen, Christina; Vetzel, Marilynn; Johnson, Theresa; Cross, Vicky; Westrick, Elaine; Qi, LongWu; Hahn, Spencer; Santhapuram, Hari Krishna; Parham, Garth; Wang, Kevin; Vaughn, Jeremy F.; Felten, Albert; Pugh, Michael; Lu, June; Klein, Patrick; Vlahov, Iontcho R.; Leamon, Christopher P.
  • imprint: Springer Science and Business Media LLC, 2020
  • Published in: Scientific Reports
  • Language: English
  • DOI: 10.1038/s41598-020-69682-9
  • ISSN: 2045-2322
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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.</jats:p>
  • Access State: Open Access