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

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold Ludovica Lospinoso Severini 1, Deborah Quaglio 2, Isabella Romeo 3 1Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, Rome, Italy 2Department of Chemistry and Technology of Drugs, Sapienza University, Piazzale A. Moro 5, Rome, Italy 3CLNS@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, Italy E-mail:isabella.romeo@uniroma1.it Hedgehog (Hh) signaling pathway inhibition has emerged in recent years as a druggable target for anticancer therapy. We previously identified Glabrescione B (GlaB), an isoflavone naturally found in the seeds of Derris glabrescens, as a novel small molecule that proved to interfere with Gli1/DNA interaction. [1] 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 (Fig 1). [2] 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 20-fold lower than single administration. Thus, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which suppresses medulloblastoma growth in vitro and in vivo providing an innovative multitargeting approach for the treatment of Hh-driven tumors. [3] 1. Infante P et al., The EMBO Journal, 2015, 34, 200-217. 2. Berardozzi S et al., Eur. J. Med. Chem., 2018, 156, 554-562. 3. Lospinoso Severini et al., Cancers, 2019, 11, 10, 1518.