Martina Garbagnoli

OC24 – Martina Garbagnoli

Drug Sciences Department, University of Pavia, Italy

BRAC ligands: novel small molecules targeting the HuR-RNA complexes with a broad-spectrum anticancer activity
Garbagnoli Martina,^1, Fontana Anna,¹ Cavassi Elena,^2,Listro Roberta,¹ Rossino Giacomo,¹ Rossi Daniela,¹ Linciano Pasquale,¹ Vaccari Melania Elettra,^1,2 Bedeschi Martina,² Campagnoli Lucrezia Irene Maria,¹ Marchesi Nicoletta,¹ Pascale Alessia,¹ Ambrosio Francesca Alessandra,³ Costa Giosuè,⁴ Alcaro Stefano^3,4, Gado Irene,⁵Vasile,⁵A. Tesei,^2, S. Collina¹ ¹ Department of Drug Sciences, Section of Medicinal Chemistry, University of Pavia, Pavia 27100, Italy Affiliation ² Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy ³ Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Campus “S. Venuta”, 88100, Catanzaro, Italy ⁴ Associazione CRISEA – Centro di Ricerca e Servizi Avanzati per l’Innovazione Rurale, 88055 località Condoleo di Belcastro (CZ), Italy ⁵ Department of Chemistry, University of Milan, Milano 20133, Italy
Abstract RNA-binding proteins (RBPs) play a key role in regulating RNA stability, fate and function with a high impact on gene expression. Among them, the Hu proteins are the most extensively studied. Specifically, HuR is involved in proliferation, differentiation and angiogenesis and it is frequently overexpressed in various types of cancers [1]. Therefore, interfering with the formation of the HuR-RNA complex represents a promising anticancer strategy [2]. In this context, our research group identified new HuR hit compounds [3], and we have now developed a new series of HuR ligands following a fragment-based drug discovery approach. This approach used protein templated dynamic combinatorial chemistry (pt-DCC) to systematically derivatize one of our previously identified hits, characterized by a benzyl resorcinol amidic core (BRAC) The compounds have been synthesised, and their anticancer properties have been evaluated on a wide panel of cancer cells, including glioblastoma, breast and pancreatic cancer models. Depending on the modifications applied on the scaffold, we were able to identify the most promising modifications for the enhancement of the anticancer activity. Therefore, we identified a series of BRAC ligands characterized by a broad anticancer activity.
References [1] Majumder M. et al. Adv. Drug Deliv. Rev. 2022, 188, 114442 [2] Wu, X. et al.. Adv. Drug Deliv. Rev. 2022, 184, 114179 [3] Della Volpe S. et al. ACS Med. Chem. Lett. 2019, 10 (4), 615–620