7R59

PARP2 catalytic domain in complex with OUL245

Summary for 7R59

• Entry DOI: 10.2210/pdb7r59/pdb
• Descriptor: Poly [ADP-ribose] polymerase 2, GLYCEROL, [1,2,4]triazolo[3,4-b][1,3]benzothiazol-6-ol, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, parp, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40180.21

Authors

Galera-Prat, A.,Maksimainen, M.M.,Lehtio, L. (deposition date: 2022-02-10, release date: 2023-01-25, Last modification date: 2024-02-07)

Primary citation

Murthy, S.,Nizi, M.G.,Maksimainen, M.M.,Massari, S.,Alaviuhkola, J.,Lippok, B.E.,Vagaggini, C.,Sowa, S.T.,Galera-Prat, A.,Ashok, Y.,Venkannagari, H.,Prunskaite-Hyyrylainen, R.,Dreassi, E.,Luscher, B.,Korn, P.,Tabarrini, O.,Lehtio, L.
[1,2,4]Triazolo[3,4- b ]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes.
J.Med.Chem., 66:1301-1320, 2023

PubMed Abstract: We report [1,2,4]triazolo[3,4-]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 analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives (OUL243) and (OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with being the most potent PARP10 inhibitor described to date (IC of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative (OUL245) inhibits poly-ARTs with a selectivity toward 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 TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.

PubMed: 36598465
DOI: 10.1021/acs.jmedchem.2c01460

Experimental method

X-RAY DIFFRACTION (2 Å)