Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors

Jennifer R Diamond; Todd M Pitts; Dana Ungermannova; Christopher G Nasveschuk; Gan Zhang; Andrew J Phillips; Stacey M Bagby; Jessica Pafford; Betelehem W Yacob; Timothy P Newton; John J Tentler; Brian Gittleman; Sarah J Hartman; John A DeMattei; James D Winkler; Michael K Wendt; William P Schiemann; S Gail Eckhardt; Xuedong Liu; Anthony D Piscopio

doi:10.1158/1535-7163.MCT-21-0455

Back

Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors

Journal article

Open access

Peer reviewed

Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors

Jennifer R Diamond, Todd M Pitts, Dana Ungermannova, Christopher G Nasveschuk, Gan Zhang, Andrew J Phillips, Stacey M Bagby, Jessica Pafford, Betelehem W Yacob, Timothy P Newton, …

Molecular cancer therapeutics, Vol.21(3), pp.397-406

03/01/2022

DOI: 10.1158/1535-7163.MCT-21-0455

PMCID: PMC9600708

PMID: 34965958

Files and links (1)

url

https://doi.org/10.1158/1535-7163.MCT-21-0455View

Published (Version of record) Open Access

Abstract

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.

Acetylation

Histone Deacetylase 1 - metabolism

Histone Deacetylase Inhibitors - pharmacology

Histone Deacetylase Inhibitors - therapeutic use

Histone Deacetylases - metabolism

Histones - metabolism

Humans

Neoplasms - drug therapy

Details

Title: Subtitle: Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors
Creators: Jennifer R Diamond - University of Colorado Anschutz Medical Campus
Todd M Pitts - University of Colorado Anschutz Medical Campus
Dana Ungermannova - University of Colorado System
Christopher G Nasveschuk - C4 Therapeutics (United States)
Gan Zhang - University of Colorado Boulder
Andrew J Phillips - University of Colorado System
Stacey M Bagby - University of Colorado Anschutz Medical Campus
Jessica Pafford - University of Colorado Anschutz Medical Campus
Betelehem W Yacob - University of Colorado Anschutz Medical Campus
Timothy P Newton - University of Colorado Anschutz Medical Campus
John J Tentler - University of Colorado Anschutz Medical Campus
Brian Gittleman - University of Colorado Anschutz Medical Campus
Sarah J Hartman - University of Colorado Anschutz Medical Campus
John A DeMattei - OnKure, Inc., Boulder, Colorado
James D Winkler - OnKure, Inc., Boulder, Colorado
Michael K Wendt - Purdue University West Lafayette
William P Schiemann - Case Western Reserve University
S Gail Eckhardt - The University of Texas at Austin
Xuedong Liu - University of Colorado System
Anthony D Piscopio - OnKure, Inc., Boulder, Colorado
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.21(3), pp.397-406
DOI: 10.1158/1535-7163.MCT-21-0455
PMID: 34965958
PMCID: PMC9600708
NLM abbreviation: Mol Cancer Ther
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: K23 CA172691 / NCI NIH HHS P30 CA046934 / NCI NIH HHS R01 AR068254 / NIAMS NIH HHS S10 OD021601 / NIH HHS S10 OD025072 / NIH HHS S10 RR026680 / NCRR NIH HHS R01 GM113141 / NIGMS NIH HHS
Language: English
Date published: 03/01/2022
Academic Unit: Internal Medicine
Record Identifier: 9984460326202771

Metrics

4 Record Views

15 Times Cited - Web of Science

See more details