On September 13, 2023 ThirtyFiveBio Limited, a biotechnology company developing first-in-class small molecule inhibitors of G protein-coupled receptor 35 (GPR35) for the treatment of gastrointestinal (GI) disease, reported that the company has been awarded a highly competitive Biomedical Catalyst (BMC) grant from Innovate UK, the UK’s innovation agency (Press release, ThirtyFiveBio, SEP 13, 2023, View Source [SID1234635148]). The grant, for a total of £495,000 (~$625,000), will fund research designed to enable the company to conduct translational studies of first-in-class GPR35 inhibitors for the treatment of gastrointestinal inflammatory diseases and cancers, ultimately allowing for the advancement of those compounds into clinical development.
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The project is focused on optimising first-of-their-kind rodent-GPR35 antagonist small molecules to support preclinical evaluation of opportunities for GPR35 inhibitors in clinically translational murine models of disease. This effort will result in a critically needed research tool capable of addressing the fact that human GPR35 inhibitors do not cross-react with rodent-GPR35 receptors and therefore cannot be deployed to many animal models of disease. The resulting small molecules will be essential in defining clinical scope of human-GPR35 inhibitors and enabling advancement of clinical candidates to proof-of-concept studies in humans.
"We believe that GPR35 inhibition represents an extremely promising and novel therapeutic approach to addressing GI cancers and inflammatory diseases, many of which need new therapies that can deliver durable results with improved tolerability. As a company at the forefront of research in this emerging area, one of our focuses is creating innovative preclinical tools for evaluating, optimising and advancing the most promising GPR35 inhibitors. Our work in this area will be significantly advanced by the grant funding received from Innovate UK and we would like to express our deep gratitude to the agency for recognizing the value of this project and providing the BMC grant," said James Westcott, Ph.D., chief executive officer of ThirtyFiveBio.
The role of GPR35 in GI diseases is genetically validated with several drug developers advancing programs designed to address the target. To date, virtually all these efforts have been focused on increasing the activity of GPR35 with targeted agonists. However, important recent scientific findings, including key insights from the ThirtyFiveBio team, support the hypothesis that GPR35 antagonism may represent a more appropriate therapeutic approach by blocking unwanted GPR35 signaling. Based on this evolved scientific perspective, supported by the company’s work with several world-leading, academic GPR35 specialists, ThirtyFiveBio is uniquely pursuing antagonism of the target with first-in-class small molecule GPR35 inhibitors.
Supporting the company’s focus on GPR35 inhibition is a collection of pre-clinical data generated by its scientists that highlights the association between GPR35 mutations and GI diseases. This includes research showing that GPR35 variants are linked to inflammatory bowel disease, and that GPR35 expression is upregulated in GI cancers. The company has also shown that pathogenic mutations of GPR35 drive its increased expression and function. Furthermore, study results have demonstrated that commonly dysregulated GI-cancer genes can be reversed by knocking out GPR35 in cancer cells. Taken together, these findings provide compelling evidence that hyperactive genetic mutations within GPR35 contribute to a range of GI disease processes, and that inhibiting GPR35 activity may have therapeutic utility in these diseases.