Candidate quality molecules were identified with suitable characteristics for further development...
A VC-backed biotech company was positioning a GPCR agonist for the treatment of diabetes and metabolic syndrome. The project was at the hit-to-lead stage, with interesting and novel chemical equity against the target of interest, but required acceleration towards candidate selection. The client challenge was two-fold; firstly how to progress the project biologically, particularly into in vivo models and secondly how to position or differentiate the project in a crowded metabolic research area.
Through our experience of the field and by conducting a full scientific literature review, an in vivo screening cascade was designed. The acute effect of test molecules on GLP-1 release was used as an in vivo filter with the best molecules being progressed to a Diet-Induced Obesity model. Care was taken to incorporate appropriate biochemical markers rather than simply relying on body weight change as a surrogate for efficacy. In particular, lipid markers were measured and HOMA assessments of pancreatic function were conducted. Using these and other measures the efficacy of molecules was demonstrated through reversal of obesity-related metabolic disturbances. Since the mechanism was known to impact on the gut-brain axis, a link was made to bariatric surgery in which the metabolic benefits are observed well before any weight loss. Further work was therefore conducted around understanding the similarities between the drug mechanism and bariatric surgery and it was shown that altered bile acid signalling was clearly a key component of both approaches.
Candidate-quality molecules were identified with suitable characteristics for further development. Additionally, a compelling narrative was constructed that was able to be used for partnering discussions and funding plans.
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