Just finished reading this fantastic review; it’s a real tour de force. The field moves so fast, and this piece does a great job of tying everything together.
I do want to poke at one specific point that’s been nagging at me, about the section on IBGs. The authors present this as a clever new category between PROTACs and molecular glues, where a single molecule bridges two domains of a protein to “glue” it to an E3 ligase.
Here’s my concern: I’m not fully convinced this isn’t just a very smartly designed bivalent PROTAC in disguise.
Let me explain. When you have a molecule with two warheads connected by a linker, it’s going to latch onto its target with incredibly high affinity; that’s bivalent binding 101. So, when IBG1 grabs both bromodomains of BRD4, it’s essentially creating a super-stable complex. The part of the molecule that’s supposed to recruit DCAF16 is now just sticking off this stable complex.
The question is: are we really seeing a new “glue” mechanism, or are we just seeing the E3 ligase being recruited to a warhead that’s being presented very efficiently because the degrader is so tightly bound?
To truly call this a “molecular glue,” I’d want to see evidence that the protein itself is being twisted into a new shape that the E3 ligase genuinely recognizes better. Right now, the data seems equally consistent with a simpler story: this is a high-affinity, bivalent PROTAC where one of the “ligands” is a binder for the target itself.
This isn’t just semantics. If I’m a chemist trying to design the next IBG, the “bivalent PROTAC” model gives me a clearer design logic than the more mysterious “glue” model.
It’s a brilliant piece of chemistry either way, but as a field, we need to be careful not to let exciting new nomenclature outpace our mechanistic understanding. I’d love to hear others’ thoughts on this.