Discovery of Novel SHIP1 Agonists

Background:

An agonist is a drug or substance that binds to a cell receptor, producing the same action as the substance that would naturally bind to the receptor. Agonists form the basis for a wide variety of therapeutics. The SH-2 containing inositol 5’ polyphosphatase 1 (SHIP1) is a multifunctional protein expressed predominantly by hematopoietic cells. Over the last decade, SHIP1 has been identified as a therapeutic target due to its role in immune cells. It also plays a role in the survival of certain cancers. For example, a SHIP1-selective inhibitor has been shown to be an effective promoter of immune responses to tumor cells, a chemotherapeutic for Blymphoid cancers, hematopoietic stem cell (HSC) mobilization, and engraftment of autologous and allogeneic HSC in murine models of disease or transplantation.

Technology Overview:

This technology consists of analogs to K306, the most potent SHIP1 agonist identified to date. K306 exhibits selectivity for SHIP1 vs. the paralog enzyme SHIP2; this activation does not require the C2 domain of SHIP1 (which other known SHIP1 agonists require). Thus, K306 represents a new class of SHIP1 agonists with a novel mode of agonism. K306 can also suppress induction of inflammatory cytokines and iNOS in macrophages or microglia, but not by their SHIP1-deficient counterparts. In addition, K306 reduces TNF-α production in vivo in an LPS-induced endotoxemia assay. Finally, K306 enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia, revealing a novel function for SHIP1 that might be exploited therapeutically in dementia.

Advantages:

•    Represents a new class of SHIP1 agonists with a novel mode of agonism. 
•    Suppresses induction of inflammatory cytokines and iNOS in macrophages or microglia.
•    Reduces TNF-α production in vivo in an LPS-induced endotoxemia assay. 
•    Offers a potential treatment for dementia.

Applications:

The primary application for this technology is the development of therapeutics based on SHIP1 agonists.

Intellectual Property Summary:

Patent application filed on 11/15/22: 63/425,601

Stage of Development:

TRL 3 - Experimental proof of concept

Licensing Status:

This technology is available for licensing.

Licensing Potential:

This technology would be of interest to anyone involved in medical research and development, including:
•    Pharmaceutical and healthcare companies.
•    Hospitals.
•    Universities.
•    Medical research laboratories.