Eisai’s Small Molecule Analog Reduced Inflammation and Injury in Mice with IBD, Study Shows

Eisai’s Small Molecule Analog Reduced Inflammation and Injury in Mice with IBD, Study Shows
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Eisai small molecule analog

A small molecule analog developed by Eisai, called ER-464195-01,  may be a potential therapy for patients with inflammatory bowel disease (IBD) by reducing infiltration of inflammatory cells, according to researchers.

Their study, “Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease,” was published in the journal Nature Communications.

IBD is a group of diseases that are characterized by repeated inflammation in the lining of the large or small intestines. One of the major processes in the development of IBD is the recruitment and infiltration of white blood cells to areas of inflammation, which leads to more inflammation and causes disease worsening.

It is well known that the activated integrin α sub-units (ITGAs), a group of proteins that are expressed on the surface of many white bloods cells, are the key to the migration and action of these cells. The treatment of IBD patients using antibodies raised against the cell surface integrin α 4 (ITGA4) has been shown to be effective.

Calreticulin (CRT) — a calcium-binding protein — is a partner in the activation of ITGAs. However, the relationship between their interaction and how they contribute to IBD has been largely unknown.

Japanese researchers, seeking to understand their relationship, conducted a screening assay to identify a compound that would dissociate CRT and ITGA4 interaction using Eisai’s compound library.

They identified ER-464195-01 as a small molecule that suppresses white blood cell adhesion by binding to CRT and inhibiting the CRT-ITGA4 interaction.

ER-464195-01 is an analog of Eisai Co.’s E6007, which is currently under investigation by EA Pharma in a Phase 2 clinical trial as a treatment for moderately active ulcerative colitis (NCT03018054).

Researchers then used a mouse model of colitis to further investigate the properties of ER-464195-01 treatment by looking at gene levels in colon samples. Interestingly, mice that were administered ER-464195-01 as a prophylactic (preventive treatment) demonstrated a reduction in the activity of pro-inflammatory genes.

Additionally, injury to the mucosal barrier and infiltration of white blood cells was significantly reduced after the treatment with ER-464195-01.

“Its [ER-464195-01] prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases,” researchers wrote.

“We propose that leukocytes [white blood cell] infiltration via the binding of CRT to ITGAs is necessary for the onset and development of colitis, and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD,” they added.

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