Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors

Pharmacological inhibition
of cathepsin S (CatS) allows for a specific
modulation of the adaptive immune system and many major diseases.
Here, we used NMR fragment screening and crystal structure-aided merging
to synthesize novel, highly selective CatS inhibitors with picomolar
enzymatic Ki values and nanomolar functional activity in human Raji
cells. Noncovalent fragment hits revealed binding hotspots, while
the covalent inhibitor structure–activity relationship enabled
efficient potency optimization.