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 synthesize...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/62cffd133d60412fb62fcc23f334889b
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spelling	oai:doaj.org-article:62cffd133d60412fb62fcc23f334889b2021-12-02T16:06:40ZPre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent10.1038/s41598-020-69682-92045-2322https://doaj.org/article/62cffd133d60412fb62fcc23f334889b2020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-69682-9https://doaj.org/toc/2045-2322Abstract 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.Joseph A. ReddyMelissa NelsonChristina DircksenMarilynn VetzelTheresa JohnsonVicky CrossElaine WestrickLongWu QiSpencer HahnHari Krishna SanthapuramGarth ParhamKevin WangJeremy F. VaughnAlbert FeltenMichael PughJune LuPatrick KleinIontcho R. VlahovChristopher P. LeamonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
description	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.
format	article
author	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
author_facet	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
author_sort	Joseph A. Reddy
title	Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
title_short	Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
title_full	Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
title_fullStr	Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
title_full_unstemmed	Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent
title_sort	pre-clinical studies of ec2629, a highly potent folate- receptor-targeted dna crosslinking agent
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/62cffd133d60412fb62fcc23f334889b
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Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent

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