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

Hedgehog (Hh) signaling 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 bearing different substitutions at the ring B. [3] 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. Interestingly, the combined administration of two different isoflavones behaving as SMO and GLI1 antagonists, respectively, in primary MB cells has shown synergistic Hh inhibition at doses that are around 20-fold lower than individual compound doses, thus leading the way to further and innovative combination therapy for the treatment of Hh-dipendent tumors. [1]. Ghirga F, et al., Bioorganic Med. Chem. Lett. 2018; 3131-3140. [2]. Infante P, et al., EMBO J. 2015; 34: 200-217. [3]. Berardozzi S, et al., Eur J Med Chem. 2018; 156:554-562.