Abstract
Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
Highlights
Tankyrase 1 and tankyrase 2 (TNKS1/2) are members of the PARP family of enzymes that control protein activities, interactions, and turnover through mono- or poly-ADPribosylation.[1]
TNKS1/2 regulate a number of target proteins, including AXIN1 and AXIN2 (AXIN1/2) in the β-catenin destruction complex resulting in WNT/β-catenin signaling pathway inhibition, and AMOT proteins in the Hippo signaling pathway resulting in YAP signaling inhibition.[1−3]
Destabilization of AXIN1/2, being a structural protein in the β-catenin destruction complex, leads to increased β-catenin levels which can be counteracted by inhibition of TNKS1/2 catalytic activity.[1,2]
Summary
Tankyrase 1 and tankyrase 2 (TNKS1/2) are members of the PARP family of enzymes that control protein activities, interactions, and turnover through mono- or poly-ADPribosylation.[1]. We replaced the benzimidazolone moiety,[10,20] as this can inflict high efflux and low solubility by a series of East-positioned amides From these amides, 20 and 21 turned out to be the most potent resulting in picomolar cellular inhibitory IC50 efficacies (Figure 2a). Moiety was replaced with the 2-fluorophenyl group of 23 resulting in acceptable efficacy compared to other substitutions (Figure 2a and Supplementary Table 1c). All possible hybrid combinations were synthesized employing the East moieties of compounds 20 and 21, a South 2-fluorophenyl group, and three different West moieties revisiting the 2-pyridyl-4-methylsulfonyl moiety as well (Table 1).[9] From these six molecules, compounds with the 1,5-naphthyridine moiety (10, 11, and 12) showed approximately 30-fold improved cellular inhibitory efficacy compared to their counterparts with the 2-pyridyl moiety (13, 14, and 15, respectively, Table 1). The large East moieties 1,5- and 1,6-naphthyridine
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