Amphista Therapeutics, based in Glasgow, Scotland, is the latest company to develop drugs called PROTACs, which are designed to make the cell degrade harmful proteins to treat cancer.
Small molecule drugs have shown incredible potential for the treatment of cancer by blocking harmful proteins in the cell. However, many promising protein targets for cancer treatments are considered ‘undruggable’, often because they have no obvious location where a small molecule drug can bind.
To take on this challenge, Amphista was founded in 2017. Spun out of the labs of protein degradation researcher Alessio Ciulli at the University of Dundee, it is based at the BioCity incubator in Glasgow.
The startup is one of many companies that have taken on the challenge of targeting so-called undruggable proteins. It designs drugs called proteolysis targeting chimeras, or PROTACs.
Broadly speaking, PROTACs are fusions of two molecules — one that binds to the target protein, and another that recruits an ‘executioner’ protein, called a ligase, to degrade the target. They have several advantages over traditional small molecule drugs, such as being able to degrade many undruggable proteins and being harder for tumors to resist via mutations to the target protein.
However, according to Nicola Thompson, CEO of Amphista, current PROTACs tend to activate ligases called E3 ligases, which can be altered by tumors to become resistant to PROTACs.
“The field has quickly realized that relying on the current ligase and associated chemistry toolbox constitutes a limitation in terms of scope of degradable targets, resistance profile, and the ability to address cell type-specific toxicity,” Thompson told me.
Amphista aims to make PROTACs that activate a different type of executioner protein machinery called the ubiquitin-proteasome system. This would give a lot more chemical tools for making PROTACs, and could help to overcome tumor resistance to E3 ligase-based PROTACs.
To fund the preclinical development of its first-in-class cancer treatments, the company raised a Series A round of €7M earlier this month and is also on the lookout for potential partnering deals. Thompson also said that Amphista aims to raise a Series B round later this year.
The field of PROTACs is a very young field, with its most advanced player, Arvinas, at phase I. This makes it a daunting task to develop a drug in this class. However, Thompson told me that it is also an opportunity to hit previously unreachable targets, and could prove cheaper to manufacture than RNAi, another type of therapy that aims to degrade disease targets.
“Targeted protein degradation will open up the druggable target space and deliver much-needed medicines, not only to treat cancer but many other diseases,” confirmed Thompson.
According to Maria Sagan, Knowledge Manager at Captor Therapeutics, the research of Ciulli’s group has contributed a lot to the field of PROTACs, and Amphista has a lot of expertise backing it.
“The interest in targeted protein degradation both from pharma and from investors is substantial, so we can expect more and more biotechs joining in the upcoming years,” she told me. “With a number of targets that remain to be drugged, there’s enough work for everyone.”
Image from Shutterstock