Richard Young: “Revisiting ‘undruggable’ targets through the lens of condensate biology”

[Transcript]

Most of us biologists have been so inspired by the structures of proteins that form with sufficient stability that we can derive the structure of how proteins fold up at atomic resolution. But we’ve really ignored the portions of proteins, when they don’t form stable structures, and yet, they’re so critical for life. They help form the compartments, they help inform their behavior, they allow the cell to be dynamic.

I like to think that if all the proteins in the cell were like the gears in a Swiss watch, that there’s only one thing it could do – they would tightly assemble with one another and do one thing at a time by crawling around in this mechanical circle. But cells need to do things in different ways. They need to assemble functional groups and then disassemble them, they need to run certain programs only at certain times, they’re not creating a continuous effort at absolutely everything they do. It’s a punctate effort, it’s due to the stimuli they see, the needs of metabolism, etc. So how does the cell do that dynamically? Well, it’s doing it through means that are not just constrained by those beautiful pictures of these highly structured parts of proteins that have so inspired us.

So now we understand that these other parts have functions, but we’ve not been inspired through pictures of them. So other kinds of inspirations have emerged that make us realize that these conserved disordered regions of proteins play really important functions. And that means they may well create the chemical environment to drug them when they go awry. So that’s why I think it’s a wonderful time to revisit targets that people have nominated because they’re so important in driving cancer, or in driving autoimmunity, or in driving other diseases. And yet, there’s been a failure because there’s been too much of a focus on that gorgeous, structured region of the protein for that drug discovery and development. Now we can focus more holistically on the whole protein, and these other very important functions they have in life. So that’s why I think it’s a perfect time to go after the not yet drugged proteins.