Palmitoylation modulators for targeted therapeutics

This technology selectively modulates palmitoylation through engineered depalmitoylases to treat pathophysiological conditions.

Unmet Need: Selective manipulation of protein palmitoylation at subcellular locations

Current methods to manipulate protein palmitoylation involve small-molecule inhibitors that lead to minimal selectivity, possible cytotoxicity, and limited efficacy. Broad-spectrum depalmitoylase inhibitors also target many different proteins across tissues, resulting in side effects. A more targeted and precise method to disrupt NRas signaling could improve treatment efficacy and patient outcomes.

The Technology: Engineered depalmitoylases with high specificity

This technology selectively modulates palmitoylation through engineered chemogenetic depalmitoylases. A feedback loop based on ERK phosphorylation allows the technology to selectively disrupt membrane association of overactive signaling proteins, including cancer-causing NRas mutants. Attachment of a high-affinity nanobody to the technology also facilitates inducible depalmitoylation as well as constitutive depalmitoylation for targeted depalmitoylation with high specificity. As such, the engineered depalmitoylase is a versatile and powerful therapeutic strategy for modulating protein palmitoylation in human disease.

This technology has been validated in rat hippocampal neurons.

Applications:

• Therapeutic strategy for cancers with Ras mutations
• Research model for cancers with Ras mutations
• Research tool for understanding the mechanisms by which palmitoylation affects protein function in disease
• Therapeutic strategy for cancer, neurodevelopment and neurodegenerative diseases, cardiovascular diseases, and chronic and neuropathic pain

Advantages:

• Selective disruption of NRas membrane association
• Specific targeting of cancer-causing NRas mutants
• Distinctive depalmitoylation modulation approach
• High specificity
• Inducible or constitutive approach
• Limited off-target effects
• Reversible manipulation of protein palmitoylation
• Versatile therapeutic application for various human diseases

Lead Inventor:

Manu Ben-Johny, Ph.D.

Patent Information:

Patent Pending (WO/2025/166210)

Related Publications:

• Jayaraman S, Kochiss A, Alcalay TL, Del Rivero Morfin PJ, Ben-Johny M. Engineered depalmitoylases enable selective manipulation of protein localization and function. Nat Commun. 2025 Apr 13; 16(1): 3514.

Tech Ventures Reference:

• IR CU24204

• Licensing Contact: Kristin Neuman