Scaffold hopping approach on the route to selective tankyrase inhibitors

Abstract

A virtual screening procedure was applied to identify new tankyrase inhibitors. Through pharmacophore screening of a compounds collection from the SPECS database, the methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold was identified as nicotinamide mimetic able to inhibit tankyrase activity at low micromolar concentration. In order to improve potency and selectivity, tandem structure-based and scaffold hopping approaches were carried out over the new scaffold leading to the discovery of the 2-(phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one as powerful chemotype suitable for tankyrase inhibition. The best compound 2-(4-tert-butyl-phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one (23) displayed nanomolar potencies (IC50s TNKS-1 = 21 nM and TNKS-2= 29 nM) and high selectivity when profiled against several other PARPs. Furthermore, a striking Wnt signaling, as well as cell growth inhibition, was observed assaying 23 in DLD-1 cancer cells.

Discovery of a Highly Selective Tankyrase Inhibitor Displaying Growth Inhibition Effects against a Diverse Range of Tumor Derived Cell Lines

“…Preparation from 13 (12 mg, 0.039 mmol) and 1-(pyridin-2-yl)piperazine hydrochloride (7.8 mg, 0.039 mmol) according to general procedure B, with the deviation that the aqueous workup was omitted, gave compound 28 as a white solid (10 mg, 57% yield). 1 (4-(Pyridin-3-yl)piperazin-1-yl)(4-(tetrazolo[1,5-a]quinoxalin-4ylamino)phenyl)methanone (29). Preparation from 13 (34.1 mg, 0.111 mmol) and 1-(pyridin-3-yl)piperazine (16.5 mg, 0.101 mmol) according to general procedure B, with the deviation that the aqueous workup was performed with ethyl acetate and the organic layer was dried over sodium sulfate, gave compound 29 as a white solid (30.8 mg, 68% yield).…”

“…Tankyrases (TNKS1 and TNKS2) belong to the family of poly­(ADP-ribose) polymerases (PARPs) and share high sequence and structural identities. They have overlapping functions playing a role in a diverse range of cellular functions, which have been the subject of comprehensive reviews. − These functions include a role in telomere homeostasis, vesicle translocation, , proteosomal assembly, mitosis, − myelination of cells in the oligodendrocyte lineage, , mediation of insulin-stimulated glucose uptake, and regulation of the Wnt/β-catenin pathway. − The relevance of a number of these pathways to cancer cell proliferation led to an increased interest in the discovery of new and selective TNKS inhibitors throughout academia and the drug discovery industry, ,− and the discovery of TNKS inhibitors has been the subject of several excellent reviews. ,,− TNKS inhibitors can be grouped into two categories. First, those that bind to the nicotinamide binding site, such as 1 (XAV939) .…”

Age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, COPD and IPF: Associations with SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 axis

“…In view of the growing interests, comparisons were also made between the expression profiles of the young IPF and old IPF with their age matched COPD subjects. Interestingly some of the well characterized genes in IPF like NOX4, TNKS2 was increased in the young IPF as compared to the young COPD patients 58,59 . Mitophagy is a well-known phenomenon occurring in both COPD and IPF and regulates the mitochondrial related damage response towards the disease 45,60 .…”

Small-Molecule Inhibitors of Wnt Signaling Pathway: Towards Novel Anticancer Therapeutics

“…As a result, 61 (2-(phenyl)-3H-benzo [4,5] thieno[3,2-d] pyrimidin-4-one) was identified as a potent structural lead demonstrating excellent inhibition against TNK. From this virtual screening approach, the most promising compound 62 (2-(4-tert-butyl-phenyl)-3Hbenzo [4,5] thieno[3,2-d]pyrimidin-4-one) was discovered which exhibited nanomolar potencies (IC 50 s TNKS1 = 21 nM and TNKS2 = 29 nM) and were found highly selective against a number of PARPs [31].…”