AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines

Michal Entin-Meer; Ada Rephaeli; Xiaodong Yang; Abraham Nudelman; Ayelet Nudelman; Daphne Adele Haas-Kogan

doi:10.1016/j.canlet.2007.01.022

AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines

Michal Entin-Meer
, Ada Rephaeli
, Xiaodong Yang
, Abraham Nudelman
, Ayelet Nudelman
, Daphne Adele Haas-Kogan

Department of Chemistry

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

15 Scopus citations

Abstract

Butyroyloxymethyl-4-phenylbutyrate (AN-113) is a novel HDACI that releases potent anti-neoplastic derivatives upon intracellular hydrolysis. The precursor of AN-113, 4-phenylbutyrate has shown promising results in a Phase I study of gliomas, and we hypothesized that AN-113 offers significant advantages over the parent drug. AN-113 demonstrates selective in vitro cytotoxicity against malignant cells while sparing normal astrocytes, effective at doses over 20-fold lower than 4-phenylbutyrate. Combining AN-113 and radiation results in additive therapeutic effects. Enthusiasm is lent to this approach by the ability of AN-113 to efficiently kill glioma cells, its bioavailability and potency when administered orally, its capacity to cross the blood-brain barrier, and its effectiveness in combination with radiation.

Original language	English
Pages (from-to)	205-214
Number of pages	10
Journal	Cancer Letters
Volume	253
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2007.01.022
State	Published - 18 Aug 2007

Bibliographical note

Funding Information:
This research was supported in part by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, NIH-PO1 NS-42927-27A2 (D.A.H.-K., K.R.L.), NIH Brain Tumor SPORE Grant P50 CA097257 (D.A.H.-K., K.R.L.), The Nancy and Stephen Grand Philanthropic Fund, the Thrasher Research Fund, and the Israel Science Foundation Grant 542/00-4 (A.R. and A.N.).

Funding

This research was supported in part by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, NIH-PO1 NS-42927-27A2 (D.A.H.-K., K.R.L.), NIH Brain Tumor SPORE Grant P50 CA097257 (D.A.H.-K., K.R.L.), The Nancy and Stephen Grand Philanthropic Fund, the Thrasher Research Fund, and the Israel Science Foundation Grant 542/00-4 (A.R. and A.N.).

Funders	Funder number
Bar Ilan University
NIH-PO1 NS-42927-27A2
National Institutes of Health	P50 CA097257
National Institute of Neurological Disorders and Stroke	P01NS042927
Thrasher Research Fund
Israel Science Foundation	542/00-4

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AN-113
Glioma
HDAC inhibitor
Radiation potentiation
γ-H2AX

Access to Document

10.1016/j.canlet.2007.01.022

Cite this

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title = "AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines",

abstract = "Butyroyloxymethyl-4-phenylbutyrate (AN-113) is a novel HDACI that releases potent anti-neoplastic derivatives upon intracellular hydrolysis. The precursor of AN-113, 4-phenylbutyrate has shown promising results in a Phase I study of gliomas, and we hypothesized that AN-113 offers significant advantages over the parent drug. AN-113 demonstrates selective in vitro cytotoxicity against malignant cells while sparing normal astrocytes, effective at doses over 20-fold lower than 4-phenylbutyrate. Combining AN-113 and radiation results in additive therapeutic effects. Enthusiasm is lent to this approach by the ability of AN-113 to efficiently kill glioma cells, its bioavailability and potency when administered orally, its capacity to cross the blood-brain barrier, and its effectiveness in combination with radiation.",

keywords = "AN-113, Glioma, HDAC inhibitor, Radiation potentiation, γ-H2AX",

author = "Michal Entin-Meer and Ada Rephaeli and Xiaodong Yang and Abraham Nudelman and Ayelet Nudelman and Haas-Kogan, \{Daphne Adele\}",

note = "Funding Information: This research was supported in part by the “Marcus Center for Pharmaceutical and Medicinal Chemistry” at Bar Ilan University, NIH-PO1 NS-42927-27A2 (D.A.H.-K., K.R.L.), NIH Brain Tumor SPORE Grant P50 CA097257 (D.A.H.-K., K.R.L.), The Nancy and Stephen Grand Philanthropic Fund, the Thrasher Research Fund, and the Israel Science Foundation Grant 542/00-4 (A.R. and A.N.). ",

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AU - Nudelman, Abraham

AU - Nudelman, Ayelet

AU - Haas-Kogan, Daphne Adele

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AB - Butyroyloxymethyl-4-phenylbutyrate (AN-113) is a novel HDACI that releases potent anti-neoplastic derivatives upon intracellular hydrolysis. The precursor of AN-113, 4-phenylbutyrate has shown promising results in a Phase I study of gliomas, and we hypothesized that AN-113 offers significant advantages over the parent drug. AN-113 demonstrates selective in vitro cytotoxicity against malignant cells while sparing normal astrocytes, effective at doses over 20-fold lower than 4-phenylbutyrate. Combining AN-113 and radiation results in additive therapeutic effects. Enthusiasm is lent to this approach by the ability of AN-113 to efficiently kill glioma cells, its bioavailability and potency when administered orally, its capacity to cross the blood-brain barrier, and its effectiveness in combination with radiation.

KW - AN-113

KW - Glioma

KW - HDAC inhibitor

KW - Radiation potentiation

KW - γ-H2AX

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ER -

AN-113, a novel prodrug of 4-phenylbutyrate with increased anti-neoplastic activity in glioma cell lines

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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