2. Academic Validation
  3. Preclinical Development of the Class-I-Selective Histone Deacetylase Inhibitor OKI-179 for the Treatment of Solid Tumors

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

  • Mol Cancer Ther. 2022 Mar 1;21(3):397-406. doi: 10.1158/1535-7163.MCT-21-0455.
Jennifer R Diamond 1,  Todd M Pitts 1,  Dana Ungermannova 2,  Christopher G Nasveschuk 2,  Gan Zhang 2,  Andrew J Phillips 2,  Stacey M Bagby 1,  Jessica Pafford 1,  Betelehem W Yacob 1,  Timothy P Newton 1,  John J Tentler 1,  Brian Gittleman 1,  Sarah J Hartman 1,  John A DeMattei 3,  James D Winkler 3,  Michael K Wendt 4,  William P Schiemann 5,  S Gail Eckhardt 6,  Xuedong Liu 2,  Anthony D Piscopio 3
Affiliations

Affiliations

  • 1 University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
  • 2 University of Colorado Boulder, Boulder, Colorado.
  • 3 OnKure, Inc., Boulder, Colorado.
  • 4 Purdue University Center for Cancer Research, Lafayette, Indiana.
  • 5 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
  • 6 Department of Oncology, Dell Medical School, University of Texas at Austin, Austin, Texas.
PMID: 34965958 DOI: 10.1158/1535-7163.MCT-21-0455
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.

Figures
Products