Our lead candidate, OKI-179, is a novel oral Class I histone deacetylase (HDAC) inhibitor for the treatment of a wide range of solid and hematological malignancies. HDAC inhibitors have shown great promise in preclinical models, however they have had little success treating solid tumors, often due to poor tolerability, inappropriate dosing regimens, poorly conceived combinations, and a lack of stratifying biomarkers. OKI-179 is designed to have improved potency, selectivity, tolerability, as well as easy combinability to overcome the historic limitations of other HDAC inhibitors. OnKure is currently conducting the Phase 1b/2 Nautilus trial of OKI-179 in combination with binimetinib in patients with NRAS mutant melanoma.

 

Program/TargetProg/Tgt
IndicationInd
DiscoveryDiscov
Lead
Optimization
Lead Opt
IND
Enabling
IND
Phase 1Ph 1
Phase 2Ph 2
CollaborationsCollab
OKI-179
NRAS Melanoma(1)
OKI-179
Oral, Selective Class I HDAC inhibitor
NRAS Melanoma(1)
In combination w/ binimetinib
Nautilus Trial
Pfizer logo
Class I HDAC inhibition has been shown to dramatically enhance the efficacy of MEK inhibitors in Ras pathway driven melanomas by coordinately suppressing two DNA repair pathways. A potential clinical biomarker that predicts responsiveness has also been identified.

(1) OKI-179 Phase 1 FIH single agent trial previously completed.

(2) Pursuant to a Clinical Trial Collaboration and Supply Agreement with Pfizer for binimetinib/OKI-179 combination; OnKure retains all OKI-179 commercial rights.

Histone Deacetylase Inhibition

Histones are proteins that associate with DNA and play an important role in gene regulation and DNA replication. Histone deacetylases, also known as HDACs, are a family of enzymes that remove acetal groups from histones and cytoplasmic proteins to regulate gene transcription and protein activity, respectively. Unlike normal cells, cancer cells may lack multiple epigenetic regulatory mechanisms and therefore, when HDACs are inhibited, it results in tumor cell cycle arrest, differentiation and apoptosis.

OKI-179 specifically inhibits Class I HDACs and causes the hyperacetylation of histones. This over acetylation activates transcription and triggers the production of proteins that have been downregulated. Importantly, many of these down-regulation events are used by cancer cells to escape from anti-cancer therapy. Thus, combining OKI-179 with targeted therapies is predicted to be more effective than using those therapies in isolation.

Our Targets

OnKure has selected and is exploring several oncology targets to expand its growing pipeline, with the goal of filing two or more INDs in the next three years. These biologically validated drivers of cancer have been chosen based on the following criteria:

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Ability to leverage our team’s expertise in kinase inhibition, cell cycle biology, signal transduction, epigenetics, and oncogenic pathway destabilization

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Target structure can be determined (structural enablement)

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Compelling biological validation

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Potential for best-in-class drug candidate

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Focused clinical proof of concept path identified

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Opportunity for portfolio synergy