Figure 1, published in Cell. Discovery of adrenergic receptor agonists that increase glucose uptake with low cAMP generation
- Novel drug candidate, ATR-258, performs well in preclinical and clinical trials in treating type 2 diabetes and obesity, without loss of muscle mass
- ATR-258 is an oral therapy, making it a straightforward, patient-friendly option over injectable therapies
- Monash University researchers provided preclinical evidence to support ATR-258 as a frontrunner candidate for type 2 diabetes and obesity
A first-in-class drug candidate for the treatment of type 2 diabetes and obesity has been found to boost glucose uptake, increase insulin sensitivity, and preserve muscle mass – mimicking the key aspects of exercise.
The new research, led by the clinical-stage Swedish biotech company Atrogi, and including researchers from the Monash Institute of Pharmaceutical Sciences (MIPS), has been published in Cell. The international team behind the research have detailed the transformative potential of Atrogi's drug candidate 'ATR-258' (referred to as compound 15 in the study), which has already successfully completed a Phase 1 clinical trial.
Bringing together interdisciplinary expertise from around the world, the authors collectively show through both preclinical and clinical studies that ATR-258 not only performs well in treating type 2 diabetes and obesity, it also reduces potential for cardiac, muscular and gastrointestinal side effects compared to standard treatments and more recently developed medications such as semaglutide (e.g. Ozempic, Wegovy).
ATR-258 is a novel drug candidate which elicits a favourable physiological response when it binds to the 'βeta-2 adrenergic receptor' (β2-AR), a G protein-coupled receptor (GPCR) known to play a critical role in regulating glucose uptake in skeletal muscle when activated.
The MIPS team, including Emeritus Professor Roger Summers, Dr Dana Hutchinson and Dr Seungmin Ham, provided preclinical evidence by identifying and determining the selectivity, potency and efficacy of select drug candidates, including ATR-258, when they bind to β2-AR.
All of the selected compounds investigated by the MIPS team performed well in preclinical models of diabetes and obesity and demonstrated a lower potential for side effects than current treatments on the market. ATR-258 emerged as the frontrunner candidate due to the way in which it not only treats diabetes and obesity, it also promotes muscle growth.
Professor Summers said the MIPS team were able to describe in the Cell study the 'pathway-selective agonists' of the β2-AR that prefer 'G-protein receptor kinase' (GRK) coupling, which is essential for promoting glucose uptake into muscle, thus underpinning ATR-258s potential as a more targeted treatment for type 2 diabetes and obesity with fewer side effects.
"GRKs play a crucial role in regulating the activity of GPCRs, so what we were looking for is drug candidates that weakly activate β2-AR and, importantly, have a preference for interacting with GRKs to improve uptake into muscle, rather than interacting with other proteins (i.e. heterotrimeric Gs proteins and b-arrestin) that are responsible for side effects and desensitisation," Professor Summers said.
"A combination of screening methods led us to the identification of these GRK-biased β2
