• 3.3 Where have all the PROTACs gone?

  • May 16 2024
  • Length: 27 mins
  • Podcast

3.3 Where have all the PROTACs gone?

  • Summary

  • A couple of years ago, PROTACs were ubiquitous. Start-ups were devising increasingly clever ways of making them, while large pharma companies were queuing up to tap into their expertise and their development programs. Proteolysis-targeting chimeras, to give them their full title, emerged as a clever and versatile way of degrading, with exquisite selectivity, disease-associated proteins that were hard to drug by conventional means.

    First described over two decades ago, by Kathleen Sakamoto, Raymond Deshaies, and Craig Crews, they comprise ‘heterobifunctional’ small molecule drugs that bind a protein of interest at one end and an E3 ubiquitin ligase at the other. This triggers the sequential addition of several ubiquitin molecules, which ‘tag’ the protein for degradation in the proteasome, a key element in the cell’s waste management machinery. Over a decade later, scientists at Celgene (now Bristol Myers Squibb) discovered that their blockbuster immunomodulatory multiple myeloma drug Revlimid (lenalidomide) was in fact a prototypical PROTAC, and this set the stage for a massive influx of investment and development across the biotech industry.

    PROTACs target intracellular proteins only, but several other analogous approaches have emerged in order to address extracellular proteins, membrane proteins or non-protein metabolites. These employ alternative targeting strategies either to direct a molecule of interest into other degradation pathways, involving lysosomal degradation or autophagy, for example, or to prevent it from fulfilling a function needed for the cell’s survival.

    The field appears to have grown quiet of late – but it has by no means run out of steam. The early leaders – chief among them Arvinas – are now in the clinic and evaluating whether their innovative science will translate into clinical benefit for patients. Most of the initial development effort is focused on cancer and, to a lesser extent, on autoimmune disease. But if PROTACs – and their relations – can be shown to work, the clinical possibilities are very wide indeed.

    Companies mentioned in this episode:
    Arvinas, Avilar Therapeutics, Bayer, Biogen, Bristol Myers Squibb, C4 Therapeutics, Celgene, Cullgen, Genentech, Halda Therapeutics, Nurix Therapeutics, Frontier Medicines, Kymera Therapeutics, Millennium Pharmaceuticals, Lycia Therapeutics, Monte Rosa Therapeutics, Novartis, Nurix Therapeutics, Paq Therapeutics, Pfizer, Roche, Sanofi, Vertex Pharmaceuticals, Vividion Therapeutics

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