Innate Immunity Targets

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Innate Immunity - Products & Services

Unlike the adaptive immune response, the innate response acts quickly and is considered the first line of defense against pathogens and foreign DNA, such as tumor cells. To be effective, the innate immune response relies on several cell types and a multitude of proteins such as interferons (INFs), which typically fight microbial infection-causing pathogens. Fighting unwanted microbes is essential, but dysregulation of the innate immune system leads to many inflammatory and autoimmune disorders. BellBrook Labs is leveraging its Transcreener technology to build enabling products and services focusing on targets found to help regulate innate immunity. Our goal is to help accelerate the discovery of potential treatments for autoimmune disease and cancer.

Transcreener cGAS Activity Assay

When free DNA is in the cytoplasm of eukaryotic cells, it can be an indication of damage or infection to the cell. This DNA triggers an immune response led by type I interferon (IFN) production. The cGAS enzyme acts as a unique sensor for double-stranded DNA. When DNA binds to cGAS it activates the enzyme producing a dinucleotide cGAMP from ATP and GTP. cGAMP created by cGAS activates STING (stimulator of interferon genes), leading to IFN immune response in the cell.

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Full-Length Human cGAS Titration

1600 Compound Pilot Screen with CD73

Transcreener CD73 Activity Assay

The Transcreener CD73 Assay measures adenosine (ADO) produced by ecto-5'-nucleotidase (also known as 5'-nucleotidase, NT5E, Cluster of Differentiation 73 or CD73). By measuring the production of ADO researchers can effectively determine the activity of the enzyme. The assay provides a powerful tool to screen entire compound libraries for CD73 modulators to help find new therapeutics for diseases such as cancer.

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Transcreener CD39 Activity Assay

The Transcreener AMP² CD39 Assay directly measures AMP produced the enzyme. By measuring the production of AMP researchers can effectively determine CD39 activity. Ectonucleotidases are plasma membrane-bound enzymes with externally-oriented active sites that metabolize nucleotides to nucleosides and are crucial for maintaining immune homeostasis. CD39 hydrolyzes ATP and ADP to AMP. AMP can further be processed to adenosine leading to a significant impact on many disease states. Recent studies have shown a key role for adenosine in immunosuppression in the tumor microenvironment, and ectonucleotidases are emerging as promising immuno-oncology targets.

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Acquire Accurate Dose-Response Measurements

cGAMP Titration with ENPP1

Transcreener ENPP1 Activity Assay

ENPP1 is a nucleotide pyrophosphatase and phosphodiesterase that regulates purinergic signaling and can degrade different nucleotides including ATP and cGAMP. The Transcreener AMP²/GMP² ENPP1 Assay directly measures the GMP and (or) AMP produced by the enzyme. ENPP1 has been identified as the primary enzyme responsible for degrading cGAMP and therefore is under intense investigation as a therapeutic target for cancer immunotherapy.

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Transcreener IKK-beta Activity Assay

IKK-beta is a serine kinase in the NF-κB pathway. IKK aids in the activation of NF-κB by phosphorylating a bound inhibitor IκBα, allowing NF-κB to enter the nucleus, in turn, activating various inflammatory responses. The signaling pathway is part of the innate immune response to bacterial and viral material, among other stimuli. Incorrect regulation can lead to a number of conditions including inflammatory autoimmune disorders and cancer.

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Human IKK-beta Titration When Converted to ADP Formed

Example Dose-Response with the Inhibitor Staurosporine

TBK1 Assay Dose Response with Staurosporine

IC₅₀ = 1.14

Transcreener TBK1 Activity Assay

More than 30 known proteins are known to interact with TBK1 on various levels. One of the most studied features is the innate immune response to foreign infectious material. Toll-like receptors activate the enzyme leading to further signaling. As a regulator of the immune response pathway to viral and bacterial material, TBK1 interacts with TANK and TRAF3. TBK1 then phosphorylates interferon regulator factors (IRFs), which activate inflammatory immune response with type I IFNs. Its role in inflammatory modulation makes TBK1 a critical target for autoimmune and neurodegenerative diseases. TBK1 also regulates aspects of cell proliferation and death, making it a key focus area in cancer research.

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Transcreener JAK3 Activity Assay

JAK3 is a tyrosine kinase that is activated by cytokine receptors. JAK3 phosphorylates and activates STATs that induce the expression of genes in the cell nucleus. JAK3 can also autophosphorylate in the presence of ATP. Because it is expressed only in hematopoietic cells, which should help to limit off-target effects, JAK3 is also being vetted for autoimmune diseases like rheumatoid arthritis. A JAK1 and JAK3 inhibitor, Tofacitinib is currently marketed by Pfizer. New specific JAK3 inhibitors could help limit the current off-target effects of the drug.

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Robust Z' Values

Enzyme Titration with the Transcreener OAS1 Assay

Transcreener OAS1 Activity Assay

As a first line of defense in the innate immune system, OAS1 is activated by viral double-stranded RNA. Upon activation, OAS1 synthesizes 2-5A from ATP which in turn activates RNase L. The result of this signaling event cleaves both viral and host RNA and in turn inhibition of protein synthesis in the cell, thus ending the replication of invading RNA viruses. The assay uses a coupling enzyme which generates AMP from the 2-5A. The AMP is then measured by the proven Transcreener AMP/GMP Assay with an FP readout.

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Assay Development and Hit-to-Lead Services

Interested in moving your program forward, but don't want to bring an assay in-house? Our scientists can help! BellBrook scientists will use their extensive biochemistry and enzymology expertise to work with you and accelerate your drug discovery program.

Lead Discovery Services Include:

Inhibitor Screening – To identify or confirm activity with the target.
Inhibitor Potency Profiling – Dose-response with target and/or related proteins. Fast IC₅₀ results.
Residence Time Measurements – Determination of k_off using ‘jump dilution’ enzymatic assay method.
Mechanism of Action Studies – Kinetic analysis to define the mode of inhibition.

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