Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules

Abstract

Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical “H–Y−Φ” motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.

[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

“…Most of the PARP inhibitors, whether inhibiting mono- or poly-ARTs, share a benzamide group as nicotinamide mimic moiety, or such a group rigidified into a cycle. 44,48 A few other scaffolds are used as benzamide bioisosters of which the triazole is also exploited. 49 Unfortunately, sharing the same pharmacophoric requirements, the compounds usually lack the desired selectivity profile.…”

“…49 Unfortunately, sharing the same pharmacophoric requirements, the compounds usually lack the desired selectivity profile. 44,50…”

“…49 Unfortunately, sharing the same pharmacophoric requirements, the compounds usually lack the desired selectivity profile. 44,50 In this paper, we initially discovered compound 1, based on a new nicotinamide mimic scaffold, TBT, which was able to inhibit multiple PARP enzymes at micromolar potency. The TBT is an underexplored scaffold in medicinal chemistry, with few examples of compounds with antifungal, 51 anticonvulsant 52 or anti-inflammatory 53 properties.…”

“…42,43 The efforts summarized above were recently reviewed documenting the high and increasing interest in the development of mono-ART inhibitors. 44…”

“…42,43 The efforts summarized above were recently reviewed documenting the high and increasing interest in the development of mono-ART inhibitors. 44 Here we report our contribution in identifying a set of compounds based on a new nicotinamide mimicking chemotype, a [1,2,4]triazolo [3,4-b]benzothiazole (TBT), able to inhibit different PARP family enzymes with submicromolar activity depending on the substitution pattern around the central core. The shortlisted compounds were profiled against most of the active human PARP enzymes leading to the most potent inhibitors for PARP10 described to date, with the best compound reaching 7.8 nM IC50 in an enzymatic assay.…”