Measuring & modeling nucleic acids is very useful and needed.

Yet, it provides a partial view.

It misses many biological processes, from signal transduction and metabolic fluxes, through enzyme activities to therapeutic effects.

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Key takeaways:
a) every second HDAC inhibitor with a phenylhydroxamic warhead inhibits MBLAC2
b) NME1-4 and HINT1 are now targetable with small molecule inhibitors
c) chemoproteomics is always good for surprises 🙂

We characterized HINT1 and NME1-4 inhibition with enzyme activity assays, molecular docking, and co-crystal structures.

As often seen with chemoproteomic approaches, we made some unexpected but exciting findings: several molecules bound to the yet undrugged proteins NME1-4 and HINT1.

Having profiled over 100 molecules, we derive rules for which HDAC pharmacophores are prone to inhibit MBLAC2. We also found nanomolar MBLAC2 inhibitors with >30-100-fold selectivity over HDACs.

Here, we profiled a hand-picked library of metalloenzyme inhibitors. This uncovered several unreported off-targets of HDAC inhibitors and confirmed MBLAC2 as a frequent off-target, also for purportedly selective inhibitors such as SW-100.

Using a chemoproteomic competition assay, we previously identified MBLAC2 as off-target of more than 20/50 profiled HDAC inhibitors (www.nature.com/articles/s41...)