PROTACs are beginning to realize their potential
Whilst mRNA lipid nanoparticle COVID-19 vaccines were stealing all the limelight in 2020-21, another conceptually new therapeutic approach was also proving itself in the clinic for the first time.
Twenty years after the concept was first conceived, protein degraders or PROTACs entered the clinic for oncology in 2019.1 The initial entry into clinic of Arvinas’ ARV-110 and ARV-471 has been rapidly followed during the last couple of years with a host of other companies entering the fray (Accutar Biotech, Bristol Myers Squibb, Dialectic Therapeutics, Foghorn Therapeutics, Kymera/Sanofi, Nurix Therapeutics, C4 Therapeutics and Cullgen).
The data emerging from those first clinical trials is answering a lot of the concerns that people had about whether the preclinical data in the labs would translate into humans. Similar to people’s reservations about RNA approaches there had been concerns that PROTACs were too far away from traditional ‘drug-like’ small molecules. They just don’t fit the rules of what a small molecule drug should look like. However, just as we are now seeing the potential for RNA therapeutics, the protein knockdown arena is wide open.
PROTACs have demonstrated that they can be tolerated in humans at doses where the protein target is degraded in tumors.2 So the principle of how they can work is proven. And although there have been some concerns expressed about tumor escape and resistance, these are no different from traditional approaches and are program-specific. Theoretically, they can be managed by the correct target and ligase selection.
So, what’s left to do?
Well, the initial PROTAC therapeutic targets were well-validated and ‘druggable’ with existing traditional small molecule approaches. The real potential of protein degradation is the ability to target a range of proteins for which a simple inhibitor won’t work – for example, protein pharmacology linked to scaffolding roles.
We are now seeing PROTACs enter the clinic for therapeutic targets which have proven difficult to drug with traditional approaches, for example, IRAK4 and STAT3 from Kymera. Many of us will be watching with interest as these programs progress.
No doubt there will be many more following
PROTAC discovery and design have become a standard tool in the arsenal of a drug discoverer. Many specialists such as our medicinal chemists in contract research services have a range of computational tools, reagents, and screening cascades now at their disposal. Leading to accelerated timelines for the discovery of novel PROTACs for new targets.
Indeed, for target validation PROTAC design is now a routine and invaluable tool for molecular biologists to support understanding of novel biological mechanisms.
This is a truly exciting time to be working in new medicine discovery. New modalities like the RNA lipid nanoparticles, CAR-T and gene therapy approaches as well as protein degradation, are making antibodies look old school.
If you’d like to learn more about PROTACs look out for our webinar where Dr. Daniel Glynn will be presenting a case study on the design of a BRPF1 PROTAC for target validation in acute myeloid leukemia (AML) cell lines harboring MLL translocations. Find out more and register here: Optimizing PROTAC design: BRPF1 degraders as a treatment for AML
References:
- Nature Reviews Drug Discovery 18, 237-239 (2019) doi: https://doi.org/10.1038/d41573-019-00043-6
- Journal of Clinical Oncology 2020 38:15_suppl, 3500-3500
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