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

Here we report [1,2,4]triazolo[3,4- b ]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogs and their crystal structures with TNKS2, PARP2, PARP14 and PARP15. Based on the substitution pattern, we were able to identify The 3-amino derivatives 21 (OUL243) and 27 (OUL232), as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14 and PARP15 at nM potencies, with compound 27 being the most potent PARP10 inhibitor described to date with an IC50 of 7.8 nM and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity towards PARP2. The scaffold does not possess inherent cell toxicity and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of the TBT scaffold for future drug development efforts towards selective inhibitors against specific enzymes. ### Competing Interest Statement The authors declare the following competing financial interests: SM, MGN, MMM, SM, OT and LL are inventors listed in a patent application regarding the disclosed inhibitors. HV, PK, BL, and LL are also inventors in granted patents and patent applications for PARP and tankyrase inhibitors. The remaining authors declare no competing interests. * ADPr : ADP-ribose BBB : blood brain barrier GI : gastrointestinal MAR : mono-ADP-ribosylation PAMPA : parallel artificial membrane permeability assay PAR : poly-ADP-ribosylation TBT : [1,2,4]triazolo[3,4- b ]benzothiazole TNKS : tankyrase