“Biased agonism” for Class-B GPCRs award

Posted on Oct 16, 2012

Carmot wins National Institute of Diabetes and Digestive and Kidney Diseases award to study drug leads with “biased agonism” for Class-B GPCRs.

San Francisco, CA – October 16, 2012.

Carmot Therapeutics announced today that it has won a two year SBIR grant from The National Institute of Diabetes and Digestive and Kidney Diseases to characterize and develop molecules that can selectively activate different GPCR signaling pathways.

More than a third of approved small molecule drugs target membrane proteins known as GPCRs. The types of interactions and their downstream effects are broad, and Carmot’s goal is to discover small molecules that engage specific subsets of GPCR signaling pathways, a concept known as biased agonism. These studies could lead to new drugs with superior pharmacological properties for the treatment of various metabolic disorders.

The award will fund the application of Carmot’s proprietary Chemotype Evolution technology to discover biased agonists of Class B GPCRs. Class B GPCRs can signal through both G-protein and beta-arrestin mediated pathways. However, the relative importance of these distinct pathways in promoting specific physiological outcomes is not understood, primarily due to a lack of pharmacological tools that differentiate between these two pathways. Carmot is in the unique position to address this question experimentally, having used its proprietary technology to identify chemically diverse agonists that show varying degrees of biased agonism.

Specifically, the project will seek to identify compounds that  engage the same GPCR in different ways, resulting in modulation of receptor signaling through activation of G-protein, beta-arrestin coupling, and/or receptor internalization. Select compounds will be used to determine the importance of biased agonism in stimulating relevant physiological outcomes using primary tissues samples from animal disease models. This information will be used to guide lead selection for further pre-clinical development.

Carmot’s Chemotype Evolution is a powerful drug discovery technology that rapidly identifies new lead molecules (www.carmot.us). Compared to conventional high-throughput screening, Chemotype Evolution can sample a greater repertoire of chemical diversity using smaller libraries of fragments. This approach provides an opportunity to tackle therapeutic targets that have been refractory to traditional small molecule drug discovery approaches.