A Project by Biotech Entrepreneur Ethan Perlstein & Magnitude Biosciences
Announced at Longevity Summit Dublin 2022 – 18th-20th September 2022
Background
One of the greatest challenges for biomedical sciences is how to slow ageing. Ageing is the major risk factor for almost all chronic diseases. And it has been estimated that one extra year of working life would increase UK GDP by 1%. Ethan Perlstein and others found that a small molecule called SMER28 was an inducer of autophagy. This earlier research used a multi-species approach to drug discovery that started with a yeast chemical modifier screen and was followed by studies in flies and human cells to further understand the mechanism of action. Subsequently, SMER28 was shown to improve models of anemia in human hematopoietic stem cells, zebrafish and mice. However, there was no known effect on Healthspan, and the target remained unknown.
Ethan identified the contract research organisation Magnitude Biosciences to investigate the efficacy of SMER28 to promote health and slow ageing, as he was familiar with how studies in the nematode C. elegans could be translatable for drug discovery, and that Magnitude Biosciences had unique capabilities and a reputation for strong data reproducibility as led by CEO David Weinkove.
Findings
Magnitude Biosciences revealed SMER28 showed toxicity at relatively low concentrations, but using their unique Automated Imaging Platform, they found a range of concentrations with a robust positive effect on Healthspan. Establishing a dose response of SMER28 also demonstrated the sensitivity of Magnitude’s technology to identify tight therapeutic windows of compound concentrations that slow ageing.
Perspective
Excitingly, the target of SMER28 was recently identified by Wrobel et al (2022) in human cells as VCP (p97). This target is well conserved in C. elegans. The homologue CDC-48.1 has 80% identity with the human protein, opening up an exciting opportunity to further study SMER28 in vivo to determine the mechanism for slowing ageing. The C. elegans cdc-48.1 mutant can be used to validate the target, determine if the toxicity remains in the absence of the target, and if so, ID any off-target effect. This work would provide a platform to discover new molecules that would be derivatives of SMER28 that hit the desired target to slow ageing but avoid the toxicity. This new safe molecule could be used to develop therapeutics to slow ageing in humans.
A word from Ethan on why he chose to work with Magnitude Biosciences and his hopes for future collaborations
Because a yeast screen enabled the discovery of SMER28, I thought it only made sense to take advantage of other model organisms to elucidate the mechanism of action and protein target of SMER28. I knew about Magnitude Biosciences and thought they'd be the perfect partner...I'm hopeful that working with Magnitude we can find a creative way to fund further work on SMER28 and its effects specifically on healthspan and longevity now that we know its target is p97/VCP.
Ethan Perlstein, Founder/CEO - Perlara PBC
The Magnitude Perspective
This project shows how we can respond quickly to test a hypothesis from an emerging longevity entrepreneur with limited resources and help them build a case for further investment. It also shows that we can reproducible detect a relatively small positive effect and build a platform that can be used to screen new derivatives to find those that are more potent and have an improved safety profile.
David Weinkove, CEO - Magnitude Biosciences