The HTS campaign performed on our proprietary chemical collection in search for PERK inhibitors returned, among others, a series of N-(3-thiazolo[5,4-b]pyridin-2-yl-phenyl)-benzenesulfonamides. Subsequent expansion identified compound 1 as a lead (IC50 = 0.27 μM). In co-crystallization with PERK (Δ loop) kinase domain the compound structure revealed that the pyridine ring establishes hydrogen bonding with the enzyme hinge region, the distal benzene ring occupies the kinase back pocket, and the sulfonamide group makes key interactions with the DFG sequence.<br/>Incidentally, a weak cross reactivity <i>vs.</i> PERK was observed for a class of N-[3-(4-pyri(mi)din-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamides under development for a different kinase inhibition program. A focused effort in this class rapidly increased PERK inhibition, leading to compound 2 (IC50 = 0.056 μM). We noticed that the common sulfonamide feature of the two series superimposes well in the PERK co-crystals, while the pyridine ring faces the kinase hinge backbone with an improved directionality in the second series. Further elaboration of this series did not significantly ameliorate the potency, while confirming the predominant role of the sulfonamide. We therefore opted for a permutation strategy of the hinge-binding moiety in the next stage of optimization. Probing a series of heterocyclic rings led to the identification of a novel prototype benzensulfonamide class, currently under further exploration within the PERK inhibition program.

Embrace the sulfonamide! The unusual pathway from the identification to the optimization of PERK inhibitors

256th National Meeting (2018)

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