I can’t help but see two very different ways of thinking when I look at the new drugs that target p53. MDM2 inhibitors, like brigimadlin, are on one side. They work under the assumption that p53 is still healthy; it’s just muted. On the other hand, there are the more ambitious projects that try to fix p53 when it is structurally broken, like eprenetapopt and FMC-220, or gene therapy that replaces it completely. They want the same thing, but their chances, risks, and timelines seem very different.
Brigimadlin is, in my opinion, the most clear and clinically sound bet. It doesn’t try to change the rules of protein folding or make strange delivery systems. It just stops MDM2, a protein that tumors use to silence p53. The best part is that we already know this interaction is real and can be targeted. Brigimadlin is being tested in cancers like liposarcoma, where MDM2 overexpression is almost always present. It is accurate without being too complicated. Yes, it will only help if TP53 is intact, but in that case, I think the “unblock the brakes” method is the best one. It’s simple, easy to measure, and less likely to fall apart because biology is so unpredictable.
Next, there is sulanemadlin, a stapled peptide with two MDM2 and MDMX. I like the ambition. Some tumors depend on MDMX more than MDM2, and drugs that only target one of them might leave that escape route open. In theory, stopping both of them could make a more general way to reactivate p53. But the truth is that peptides are very hard to work with in the clinic, and sulanemadlin’s safety problems show that. I’m not sure that the molecule, as it is, can win, but I wouldn’t completely rule out the idea of a dual target. If someone could figure out how to make it safe and deliver it, it could be very useful. But that’s a big “if.”
I see both the most scientific elegance and the most risk in the mutant p53 reactivators, such as eprenetapopt and FMC-220. Fixing a broken tumor suppressor at the protein level is like trying to fix a car engine while it’s running: it’s possible in theory, but even small mistakes can cause it to fail completely. Eprenetapopt has shown some promise, but the results have not always been the same. FMC-220 is more focused on the Y220C mutation, which could make it much stronger for the small number of patients who have that exact variant. It’s like a sniper shot instead of a broad-spectrum drug. I like that way of thinking, but it won’t be a “p53 cure-all” because it only works in a few cases.
Gene therapy like Gendicine is brave, and to be honest, it still feels like science fiction in most places outside of China. The thought of giving someone a working TP53 directly is almost too good to be true. But the problem that has kept this field from moving forward for decades is getting it into all tumor cells and only tumor cells. Oncolytic viruses work in a similar way, using defects in the p53 pathway to sneak into tumor cells and kill them. They’re smart, but again, not something I’d put ahead of the more targeted strategies that don’t depend on delivery as much.
If I had to choose the method that seems most likely to work in the next five years, I would choose the MDM2 inhibition route, specifically brigimadlin. It’s a targeted fix for a very clear and testable problem in some cancers. It’s the one that seems to have the shortest path from “mechanism” to “measurable clinical benefit.” That doesn’t mean you should give up on the others; not at all. I think mutant reactivators and dual MDM2/MDMX blockers are worth investing in, but I would see them as high-risk, high-reward plays instead of the main part of a p53 drug strategy.
That’s where I stand, but reasonable people could see it differently on this subject. Should you stick with the method that is most likely to work soon, even if it only helps a small number of patients? Or is it better to spread resources across riskier, more complicated strategies that could one day help a lot more people reactivate p53? My gut tells me to start with the surest path and work my way out, but I’d like to know if anyone else thinks the moonshot should be a priority right now.
YP53 
Leave a comment