Race Oncology Ltd (ASX:RAC, OTC:RAONF) has wrapped up a drug discovery program at Monash University’s Fragment Platform (MFP) targeting the fat mass and obesity-associated protein or FTO, making some significant findings along the way.
The program used fragment-based screening by NMR to identify 39 molecular candidates (‘hits’) that specifically bind to the m6A RNA demethylase protein, FTO. These had their binding confirmed by multiple NMR methods and surface plasmon resonance.
NMR fragment screening or spectroscopy offers an alternative to conventional high throughput screening and can identify drug-like molecules that bind outside the enzyme activity site with the potential to regulate protein activity.
New drugs on horizon
The screening confirmed that FTO-binding chemical scaffolds provide a platform for the development of novel and patentable molecules with the potential to become new drugs that specifically target the m6A RNA epigenetic pathway.
This discovery positions Race to develop potent and selective new structurally unique FTO inhibitors – patentable, first-in-class drugs targeting the protein, which have the potential to expand into applications beyond cancer therapies.
RNA epigenetics dysregulation (loss of control) of RNA epigenetics is a key driver of several metabolic diseases and many cancers.
One of the key proteins in this dynamic RNA regulatory system is the ‘Fatso’ or FaT and Obesity-associated protein (FTO), which acts as a global regulator of m6A RNA levels.
There is, understandably, significant scientific and pharmaceutical industry interest in developing FTO inhibitor drugs as potential new cancer treatments.
Identification of selective FTO inhibitors is complicated by the high similarity between the enzymatic active sites of FTO and closely related members of the ALKBH protein family.
In 2022, Race commissioned the Monash Fragment Platform (MFP) library, a curated collection of chemical fragments, to perform an NMR-based fragment screen to identify unique chemical structures that bind to the FTO or ALKBH5 proteins.
Cutting edge of oncology
Race vice president of Research Prof. Mike Kelso said: “Identification of chemical ‘hits’ that bind to a protein target of interest is a critical step in modern drug discovery.
“Our successful FTO program at Monash provides Race with valuable new IP in the RNA epigenetics space, an enormously exciting area at the cutting-edge of oncology research and drug development.”
Race Oncology plans to undertake a ‘hit-to-lead’ medicinal chemistry campaign to convert these validated fragments into lead drug candidates.
This process involves optimising the chemical structures to enhance FTO inhibitory potency and selectivity, ensuring efficacy in animal cancer models, minimising toxicity and achieving favourable metabolic profiles.
Race is in the process of deciding whether to proceed with this resource-intensive phase.