I think there may be quite a bit of room for improving this scaffold. It is unclear that the quinolone is the best group to insert in the P1 pocket and it is possible/likely that other functional group like a simple pyridine or a triazole may have a better affinity for this pocket. Also, the group inserting into the P2 pocket may be optimized further; a substituted benzyl ring may improve both affinity and solubility.
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Hi @Ste_Pia,
Sorry, I am very behind, but I really appreciate the detailed writeup. The scaffold is interesting and obviously builds on quite a few of the active quinolones in P1 we have seen in our data. Interestingly, we have observed that the quinolones such as EDJ-MED-6af13d92-3 and ERI-UCB-a0b0dbcb-2 can have quite different linkers between P1 and P2 compared to the canonical aminopyridine scaffold making up our main series.
We have a few designs that have been ordered and some assayed already attempting to change that linker (see ERI-UCB-a0b0dbcb for example), but the 3-cyano pyridine is definitely not something we have probed. And yes, we have observed that the isoquinoline is more potent that the quinolone in P1, which has been really hard to get in a molecule under 1 uM. Thanks again!