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

Area of Science:

• Epigenetics and Cancer Biology
• Medicinal Chemistry and Drug Discovery
• Pharmacology and Therapeutics

Background:

• Histone deacetylases (HDACs) are crucial for epigenomic regulation, and their dysregulation is implicated in various human cancers.
• Current HDAC inhibitors show limited efficacy in solid tumors due to poor selectivity, narrow therapeutic windows, and lack of biomarkers.

Purpose of the Study:

• To report the discovery and preclinical development of OKI-179, a novel, orally bioavailable, class I-selective HDAC inhibitor.
• To evaluate the antiproliferative and antitumor potential of OKI-179 in preclinical cancer models.

Main Methods:

• Development of OKI-179 as a thioester prodrug of the active metabolite OKI-006, optimizing physiochemical properties while maintaining potency and selectivity.
• In vitro assessment of OKI-005 (predecessor) for antiproliferative activity, apoptosis induction, and histone acetylation.
• In vivo evaluation of OKI-179 in preclinical cancer models, assessing antitumor activity, pharmacokinetics, and pharmacodynamics.

Main Results:

• OKI-005 exhibited in vitro antiproliferative effects, apoptosis induction, and increased histone acetylation, confirming target engagement.
• OKI-179 demonstrated significant antitumor activity in preclinical cancer models.
• OKI-179 possesses a favorable pharmacokinetic profile and exhibits on-target pharmacodynamic effects.

Conclusions:

• OKI-179 is a potent, orally bioavailable, class I HDAC inhibitor with broad efficacy against solid tumors.
• The favorable preclinical profile supports the ongoing first-in-human Phase I clinical trial of OKI-179 for solid tumors and hematologic malignancies.