GPCR-Heterodimer Identification Technology (GPCR-HIT) and Its Applications

GPCR-HIT

Dimerix's GPCR-Heterodimer Identification Technology (GPCR-HIT) is a proprietary cell-based assay that provides a rapid, inexpensive and unambiguous way to systematically identify GPCRs that form heterodimers and compounds that activate them. GPCR-HIT will become a critical tool enabling new compounds to be assessed for undesired activities prior to undertaking expensive animal and human trials. The assay also, for the first time, enables high throughput screening campaigns to be conducted against heterodimer targets.

GPCR-HIT has been demonstrated using several model GPCR systems to confirm GPCR heterodimer pairs postulated in the scientific literature. In addition, GPCR-HIT has been used to identify multiple, novel heterodimers with clinical and commercial relevance.

Applications of GPCR-HIT

It is now accepted that a drug, in addition to acting directly on a GPCR, can activate a GPCR indirectly via a heterodimer pair (Diagram 1). Understanding when a GPCR drug activates a GPCR indirectly through the heterodimer formation can explain side effects, improve existing drugs and lead to new GPCR drugs.

GPCR A, when stimulated by drug A, gives Effect A (left panel). However, when GPCR A is found to function as a heterodimer with GPCR B, then drug A will not only elicit Effect A, but may also indirectly trigger GPCR B for Effect B, and potentially a unique heterodimer effect, Effect AB (right panel).

Understanding the indirect activation of drug A cannot be done through conventional drug screening programs which would screen drug A directly against GPCR B and report no activity. Dimerix's technology now enables drug A to be screened for heterodimer activity (against known GPCR heterodimers and novel heterodimers that can be rapidly identified using the technology).

There are several commercial opportunities raised by this:

1. Market Expansion: A known drug A can potentially be utilised to activate GPCR B and therefore treat a condition normally required to be treated using a drug targeting GPCR B. This provides a new market opportunity for drug A.

2. Receptor Deorphanisation: Many GPCRs have no ligand identified to activate them, although the receptors may have been validated as a target. These types of receptors are known as orphan receptors. In Diagram 1, GPCR B could represent an orphan receptor that is effectively de-orphanised by drug A through the identification of the heterodimer.

Diagram 2: Use of a GPCR B specific antagonist αB

3. Management of Side Effects: Where Effect A is the only desired effect, then Effects B and AB may represent causes of unwanted side effects. Knowledge of the heterodimer activation means strategies can be developed to manage these side effects. For instance, as illustrated in Diagram 2, a GPCR B specific antagonist, αB, may be introduced in combination with drug A. Even a modest reduction in side effect profile achieved through this approach would result in new patents around the compound and an extension of its market life.

Diagram 3: Combination therapy of drug B and drug A

4. Combination Therapy: Where indirect activation of GPCR A by drug B is additive in the presence of drug A (and / or vice versa), potential exists to improve outcomes by a combination therapy of drug B and drug A which together can provide an enhanced response at lower doses (Diagram 3).

Note that these first four applications represent potential opportunities to expand the indications and improve the safety and efficacy of existing marketed compounds. Improvement of existing drugs is often termed a product life extension strategy and provides a fast route to market (and revenue generation).

Diagram 4: Heterodimer specific drug AB giving only Effect AB

5. New GPCR Targets: GPCR heterodimers will become the next generation of targets for high-throughput screening programs to identify heterodimer specific drugs (Diagram 4).