Identification of Honokiol‐Based Scaffold to Design Tankyrase 1/2 Inhibitors by <i>In Silico</i> and <i>In Vitro</i> Studies

Recently, we identified magnolol bioinspired derivatives as new Tankyrase 1/2 (TNKS1/2) inhibitors by our Inverse Virtual Screening protocol. Based on these findings, in the present contribution, we enlarged our investigation of neolignans to the natural product honokiol (1) and a group of its analogues (2-8). By integrating in silico analysis and Surface Plasmon Resonance experiments, we investigated the binding of tested compounds against biological target under investigations. Specifically, 1 (honokiol), 2, 6 and 7 bound TNKS2 with a K_D in the low nanomolar range, whereas 3-5 and 8 showed absence of affinity for the macromolecule. Furthermore, we also proved the binding specificity of 1 and 7 against TNKS2, while 2 and 6 were found to be also TNKS1 binders. The congener 4 was identified as specific TNKS1 ligand. Promising antiproliferative activity in A549 cancer cell line were obtained for 1 and 6, with honokiol (1) presenting a higher potency than the well-known TNKS2 inhibitor XAV939. Collectively, these outcomes suggest that the honokiol-based scaffold can be employed to design novel anti-cancer therapeutic agents.