Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study

Victoria C. Yan; Kristine L. Yang; Elliot S. Ballato; Sunada Khadka; Prakriti Shrestha; Kenisha Arthur; Dimitra K. Georgiou; Mykia Washington; Theresa Tran; Anton H. Poral; Cong Dat Pham; Matthew J. Yan; Florian L. Muller

doi:10.1021/acsmedchemlett.0c00203

Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study

Victoria C. Yan, Kristine L. Yang, Elliot S. Ballato, Sunada Khadka, Prakriti Shrestha, Kenisha Arthur, Dimitra K. Georgiou, Mykia Washington, Theresa Tran, Anton H. Poral, Cong Dat Pham, Matthew J. Yan, Florian L. Muller

Cancer Systems Imaging

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.

Original language	English (US)
Pages (from-to)	1484-1489
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	7
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00203
State	Published - Jul 9 2020

Keywords

Pro-drug
glycolysis inhibitor
hypoxia
targeted therapy

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.0c00203

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title = "Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study",

abstract = "Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.",

keywords = "Pro-drug, glycolysis inhibitor, hypoxia, targeted therapy",

author = "Yan, {Victoria C.} and Yang, {Kristine L.} and Ballato, {Elliot S.} and Sunada Khadka and Prakriti Shrestha and Kenisha Arthur and Georgiou, {Dimitra K.} and Mykia Washington and Theresa Tran and Poral, {Anton H.} and Pham, {Cong Dat} and Yan, {Matthew J.} and Muller, {Florian L.}",

note = "Funding Information: We thank Kumar Kalhurachchi for NMR assistance. This work was supported by the American Cancer Society RSG-15-145-01-CDD (F.L.M.) and the National Comprehensive Cancer Network YIA170032 (F.L.M.). Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = jul,

day = "9",

doi = "10.1021/acsmedchemlett.0c00203",

language = "English (US)",

volume = "11",

pages = "1484--1489",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

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TY - JOUR

T1 - Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase

T2 - Proof of Concept Study

AU - Yan, Victoria C.

AU - Yang, Kristine L.

AU - Ballato, Elliot S.

AU - Khadka, Sunada

AU - Shrestha, Prakriti

AU - Arthur, Kenisha

AU - Georgiou, Dimitra K.

AU - Washington, Mykia

AU - Tran, Theresa

AU - Poral, Anton H.

AU - Pham, Cong Dat

AU - Yan, Matthew J.

AU - Muller, Florian L.

N1 - Funding Information: We thank Kumar Kalhurachchi for NMR assistance. This work was supported by the American Cancer Society RSG-15-145-01-CDD (F.L.M.) and the National Comprehensive Cancer Network YIA170032 (F.L.M.). Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/7/9

Y1 - 2020/7/9

N2 - Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.

AB - Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.

KW - Pro-drug

KW - glycolysis inhibitor

KW - hypoxia

KW - targeted therapy

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Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study

Abstract

Keywords

ASJC Scopus subject areas

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