Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach

Abstract

A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 displays high target affinity on tankyrase 1 and 2 with biochemical and cellular IC values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Critical for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and phenyl linker.

Novel Pyrimidinone Derivatives Show Anticancer Activity and Induce Apoptosis: Synthesis, SAR and Putative Binding Mode

“…between ring keto and SER1221 hydroxyl in the nicotinamide subpocket, amide keto and TYR1213 backbone keto in the adenosine subpocket, while exhibited π‐π stacking/hydrophobic interactions with binding site amino acids, namely TYR1224, HIS1184, PHE1188 and HIS1201. These interactions are reported to be vital for enzyme inhibition based on the X‐ray structures of active compounds . However, as expected, an H‐bonding interaction with GLY1185 in the nicotinamide subpocket was lost in case of new compounds ( 12 and 22 ) because of the absence of ‐NH group that is present in known ligands 26 and 27 .…”

“…Recently, tankyrase inhibitors have been identified as useful chemical probes and potential lead compounds . We found that the synthesized compounds possessed similarity with ligands reported as tankyrase‐1 inhibitors binding to both the nicotinamide subpocket and the adenosine subpocket and X‐ray crystal structures (PDB‐ID: 4I9I) are available in the Protein Data Bank (www.rcsb.org). In order to study the putative binding mode of our selected compounds ( 12 and 22 ), we employed flexible docking studies using InducedFit Docking (IFD) modules (Schrödinger suite) into the active site of this enzyme.…”

Crystal structure of 3-(5-amino-1H-1,2,4-triazol-3-yl)-1-(piperidin-1-yl)propan-1-one, C10H17N5O

“…Interest in molecules related to the title compound stem from the significant biological activity exhibited by 1,2,4-triazoles [6,7]. This interest prompts investigations into efficient synthesis of these derivatives and in this context, recently two new complementary pathways for the synthesis of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl) propanamides based on microwave technology were described [5].…”

Discovery of Novel Inhibitor for WNT/β-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening

“…The human tankyrase protein family consists of TNKS-1 and TNKS-2, featuring a catalytic ARTD domain at the C-terminus of 89% of overall sequence identity. The structure has been resolved for the TNKS inhibitor development [38,47,48]. The crystal structures of TNKS-2 in a complex with 3 of 17 XAV939 revealed that the tankyrase inhibitor interacts with the NAD + binding groove of the catalytic domain [49].…”