Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Hedgehog (Hh) signaling pathway inhibition has emerged in recent years as a druggable target for anticancer therapy. [1] We previously identified Glabrescione B (GlaB), an isoflavone naturally found in the seeds of Derris glabrescens (Leguminosae), as a novel small molecule that proved to interfere with Gli1/DNA interaction. [2] We provided the total synthesis of GlaB based on the deoxybenzoin route, allowing the structure activity relationship elucidation through the preparation of a small-size focused library of isoflavones. Target preference has been achieved by the introduction of specific bulky substitutions at meta position (targeting Gli1) or para position (targeting Smo) of the isoflavone’s ring B that is able to block the pathway respectively at the downstream effector Gli1 or the upstream receptor Smo. [3] Interestingly, the combined administration of two different isoflavones behaving as Smo and Gli1 antagonists in primary medulloblastoma cells has shown synergistic Hh inhibition at doses that are around 20-fold lower than single administration, thus leading the way to further and innovative combination therapy for the treatment of Hh-dipendent tumors. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Thus, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level and suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1 providing a novel mechanism of action in Hh inhibition. Our study encourages the use of a multitargeting approach for the treatment of Hh-driven tumors and provides significant support in oncology research for the development of new clinically relevant Hh inhibitors. References: [1]. Ghirga F et al. (2018). Bioorganic Med. Chem. Lett. 28: 3131-3140. [2]. Infante P et al. (2015). The EMBO Journal 34: 200-217. [3]. Berardozzi S et al. (2018). Eur. J. Med. Chem. 156: 554-562. [4]. Lospinoso Severini et al. (2019). Cancers 11. 1518.