Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
| Autor: | Iontcho Radoslavov Vlahov, Garth L. Parham, Patrick J. Klein, Elaine Westrick, June Lu, Christopher P. Leamon, Christina Dircksen, Marilynn Vetzel, Jeremy F. Vaughn, Albert Felten, Melissa Nelson, Vicky A. Cross, Longwu Qi, Kevin Wang, Hari Krishna Santhapuram, Joseph A. Reddy, Theresa Johnson, Spencer Hahn, Michael Pugh |
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| Rok vydání: | 2020 |
| Předmět: |
Drug Evaluation
Preclinical Triple Negative Breast Neoplasms Pharmacology Ligands KB Cells Mice chemistry.chemical_compound Drug Delivery Systems media_common Ovarian Neoplasms Vintafolide Multidisciplinary Drug discovery Folate Receptors GPI-Anchored Cross-Linking Reagents Oncology Paclitaxel Folate receptor Medicine Female medicine.drug Drug Alkylating Agents Science media_common.quotation_subject Mice Nude Antineoplastic Agents Article Inhibitory Concentration 50 Dogs Folic Acid medicine Animals Humans Vinca Alkaloids IC50 Cisplatin DNA DNA Crosslinking Agent Xenograft Model Antitumor Assays In vitro Endometrial Neoplasms Rats Mice Inbred C57BL chemistry Drug Design Cattle |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-69682-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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