Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors
©2021 American Association for Cancer Research..
Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I-selective HDAC inhibitor, OKI-179. OKI-179 and its cell active predecessor OKI-005 are thioester prodrugs of the active metabolite OKI-006, a unique congener of the natural product HDAC inhibitor largazole. OKI-006, OKI-005, and subsequently OKI-179, were developed through a lead candidate optimization program designed to enhance physiochemical properties without eroding potency and selectivity relative to largazole. OKI-005 displays antiproliferative activity in vitro with induction of apoptosis and increased histone acetylation, consistent with target engagement. OKI-179 showed antitumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Molecular cancer therapeutics - 21(2022), 3 vom: 01. März, Seite 397-406 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Diamond, Jennifer R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.04.2022 Date Revised 28.10.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1535-7163.MCT-21-0455 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM335017738 |
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| 245 | 1 | 0 | |a Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors |
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| 500 | |a Date Revised 28.10.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 American Association for Cancer Research. | ||
| 520 | |a Histone deacetylases (HDACs) play critical roles in epigenomic regulation, and histone acetylation is dysregulated in many human cancers. Although HDAC inhibitors are active in T-cell lymphomas, poor isoform selectivity, narrow therapeutic indices, and a deficiency of reliable biomarkers may contribute to the lack of efficacy in solid tumors. In this article, we report the discovery and preclinical development of the novel, orally bioavailable, class-I-selective HDAC inhibitor, OKI-179. OKI-179 and its cell active predecessor OKI-005 are thioester prodrugs of the active metabolite OKI-006, a unique congener of the natural product HDAC inhibitor largazole. OKI-006, OKI-005, and subsequently OKI-179, were developed through a lead candidate optimization program designed to enhance physiochemical properties without eroding potency and selectivity relative to largazole. OKI-005 displays antiproliferative activity in vitro with induction of apoptosis and increased histone acetylation, consistent with target engagement. OKI-179 showed antitumor activity in preclinical cancer models with a favorable pharmacokinetic profile and on-target pharmacodynamic effects. Based on its potency, desirable class I HDAC inhibition profile, oral bioavailability, and efficacy against a broad range of solid tumors, OKI-179 is currently being evaluated in a first-in-human phase I clinical trial with plans for continued clinical development in solid tumor and hematologic malignancies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a Pitts, Todd M |e verfasserin |4 aut | |
| 700 | 1 | |a Ungermannova, Dana |e verfasserin |4 aut | |
| 700 | 1 | |a Nasveschuk, Christopher G |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Gan |e verfasserin |4 aut | |
| 700 | 1 | |a Phillips, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Bagby, Stacey M |e verfasserin |4 aut | |
| 700 | 1 | |a Pafford, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Yacob, Betelehem W |e verfasserin |4 aut | |
| 700 | 1 | |a Newton, Timothy P |e verfasserin |4 aut | |
| 700 | 1 | |a Tentler, John J |e verfasserin |4 aut | |
| 700 | 1 | |a Gittleman, Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Hartman, Sarah J |e verfasserin |4 aut | |
| 700 | 1 | |a DeMattei, John A |e verfasserin |4 aut | |
| 700 | 1 | |a Winkler, James D |e verfasserin |4 aut | |
| 700 | 1 | |a Wendt, Michael K |e verfasserin |4 aut | |
| 700 | 1 | |a Schiemann, William P |e verfasserin |4 aut | |
| 700 | 1 | |a Eckhardt, S Gail |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xuedong |e verfasserin |4 aut | |
| 700 | 1 | |a Piscopio, Anthony D |e verfasserin |4 aut | |
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