Bocodepsin 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. Bocodepsin 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 bocodepsin in combination with binimetinib in patients with NRAS mutant melanoma.

 

Program/Target Prog/Tgt
Indication Ind
Discovery Discov
Preclinical Preclin
Phase 1 Ph 1
Phase 2 Ph 2
Collaborations Collab
Bocodepsin
{em}NRAS{/em} Melanoma{sup}(1){/sup}
Bocodepsin
Oral, selective class I
HDAC inhibitor
{em}NRAS{/em} Melanoma{sup}(1){/sup}
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) Bocodepsin Phase 1 FIH single agent trial previously completed.

(2) Pursuant to a Clinical Trial Collaboration and Supply Agreement with Pfizer for binimetinib/bocodepsin combination; OnKure retains all bocodepsin 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.

Bocodepsin 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 bocodepsin 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