Cryo-EM-guided pocket merging yields an oral allosteric SLC6A19 inhibitor
- Virtual screening against the allosteric pocket seen in the SLC6A19/cinromide cryo-EM structure gave a starting hit.
- A second, partially overlapping pocket from a further cryo-EM structure inspired merged analogues, leading to a potent, selective, orally bioavailable compound 20.
- Compound 20 was weaker on mouse than on non-human primate SLC6A19, yet oral dosing raised urinary amino acid excretion dose-dependently.
💡 Points
Membrane transporters rarely give such a clean example of structure-driven design: two cryo-EM pockets, one merged series, in vivo pharmacodynamics from a simple urinary readout. The mouse potency shift is the practical snag for efficacy models, so the primate retention is reassuring. Next I'd want to know the margin for amino acid depletion.