New antibody-drug conjugates charged with unconventional payload Demetra Zambardino, F. Migliorin, F. Manetti, M. Taddei, E. Petricci Università degli Studi di Siena, Italy Antibody-drug conjugates (ADCs) are a rapidly expanding class of drug delivery systems consisting of a (mAb) connected by a properly design linker, to a potent therapeutic agent known as payload. These systems consent a high selective delivery of a specific drug to the target tissue, thereby minimizing its off-target toxicity in health tissues, potentially leading to an improved therapeutic index. With 14 ADCs currently approved by the Food and Drug Administration (FDA) for cancer treatment, and more than 100 ACDs in clinical trials, this technology represents a very innovative and efficient approach in the selective drug delivery field. The linker plays an important role as it needs to be stable in blood circulation and to let the drug be released once the ADC is internalized into tumor cells [1] . We recently discovered that is not mandatory to charge a mAb with a very cytotoxic payload to obtain an efficient ADC [2-4]. Going on with these findings, we here present the design and synthesis of ADCs charged with modulators of the Hedgehog signaling pathway, an important target in hedgehog dependent tumors such as glioblastoma, basal cell carcinoma, melanoma, and many others [5-7]. A broad range of inhibitors of the hedgehog signaling pathway is reported in literature: some of them, as Vismodegib and Saridegib, are already used in therapy. Furthermore, their application is limited because of the early tumor resistance frequently observed. To overcome tumor resistance by using a more efficient delivery system such as an ADC, our efforts to develop this new class of bioconjugates is here reported with a special attention on the use of different cleavable and non- cleavale linkers properly designed in our group [8] . References 1. Chudasama, V.; Maruani, A.; Caddick, S.; Nat. Chem . 2016 , 8 , 114-119. 2. Cianferotti, C.; Faltoni, V.;Cini, E.; Ermini, E.; Migliorini, F.; Petricci, E.; Taddei, M.; et al. , G . Chem. Commun ., 2021 , 57 , 867- 870. 3. Cini, E.; Faltoni, V.; Petricci, E.; Taddei, M.; Salvini, L.; Giannini, G.; Vesci, L.; Milazzo, F. M.; Anastasi, A. M.; Battistuzzi, G.; De Santis, R., Chem. Sci. , 2018 , 9 , 6490–6496. 4. Milazzo, F. M.; Vesci, L.; Anastasi, A. M.; Chiapparino, C.; Rosi, A.; Giannini, G.; et al. Front. Oncol. 2020 , 9, 1534. 5. Pietrobono, S.; Gagliardi, S.; Stecca, B.; Front. Genetics 2019 , 10 , 556. 6. Vesci, L.; Milazzo, F. M.; Stasi, M. A.; Pace, S.; Manera, F.; Tallarico, C.; Cini, E.; Petricci, E.; Manetti, F.; De Santis, R.; Giannini, G.; Eur. J. Med. Chem . 2018 , 157 , 368-379. 7. Manetti, F.; Maresca, L.; Crivaro, E.; Pepe, S.; Cini, E.; Singh, S.; Governa, P.; Maramai, S.; Giannini, G.; Stecca, B.; Petricci, E. ACS Med. Chem. Lett. 2022 , 13 , 1329-1336 8. Migliorini, F.; Cini, E.; Dreassi, E.; Finetti, F.; Ievoli, G.; Macrì, G.; Petricci, E; Rango, E.; Trabalzini, L.; Taddei, M. ChemComm 2022 , 58 , 10532-10535.
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