Small molecules that target messenger RNA have therapeutic potential, but the field still lacks an unqualified success. Companies differ on how to move the resurgent field forward
. “The most urgent thing right now is to take on targets that have a biological de-risk, which means we know that that target is driving a disease,” says Disney. “Those [compounds] are the ones we should be front-loading to get into patients. And then, you know, we can expand after that.
But another bottleneck with phenotypic screening is figuring out what RNA the compound is hitting. “In order to do med chem on that stuff, you really have to have a meaty target deconvolution part of the platform,” says Disney. Phenotypic screening “is exciting, because you get directly functional molecules at the beginning, but you’ve got to find what the targets are.”
Another bottleneck is figuring out how a compound that does bind the RNA and alters biology is actually working. The mechanism may not even be related to the binding event. Even if it is, “is it directly interfering with the translation machinery? Is it affecting the half-life of the mRNA? Have you turned on some decay pathway? Is it splicing?” asks Ribometrix co-founder and VP of biology Katie Warner. “The list goes on and on.” Standard anti-enzyme drug discovery doesn’t have this problem.
“The field is moving towards accepting the view that was proposed in that review,” says Weeks. But that’s not clear. Expansion Therapeutics, for example, is targeting the CUG trinucleotide repeats in RNA that cause myotonic dystrophy. “We have a ton of data to show that you can target repeat expansions or oncogenic RNAs pretty selectively with small molecules, with high affinity and specificity,” says Disney. Weeks doesn’t rule out this approach.
Most biotechs in this space, though, don’t use AI for this purpose, at least for now. They do use it to verify other structural findings and to enrich their chemical libraries for RNA-binding chemical matter. “There’s a lot of hype in AI,” says Disney. “We’re going to have to really see what that can deliver on. But it’s promising.”
Arrakis is developing small-molecule degraders called NUTACs, or nucleic acid-targeting chimeras. Like PROTACs, they are small molecules that link an RNA binder to a host effector molecule that triggers degradation. Gilman won’t say which host effectors Arrakis is employing. “There’s definitely a bit of a footrace to try to find them first,” he says.or ribonuclease-targeting chimeras.
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