Author: Bordoni, Martina ; Massa, Carmen ; Catalanotti, Bruno ; Lupia, Antonio ; Rapacciuolo, Pasquale ; Graziosi, Luigina ; Urbani, Ginevra ; Marchianò, Silvia ; Natalizi, Nicola ; Bellini, Rachele ; Di Giorgio, Cristina ; Fiorucci, Stefano ; Lachi, Ginevra ; Finamore, Claudia ; Distrutti, Eleonora ; Moraca, Federica ; Biagioli, Michele ; Donini, Annibale ; Zampella, Angela ; Morretta, Elva ; Sepe, Valentina ; Chiara Monti, Maria

The leukemia inhibitory factor (LIF) is member of interleukin (IL)-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFRβ subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.

14 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery and Structure–Activity Relationships of Novel ssDAF-12 Receptor Modulators

Q1 · MEDICINE

Article

Author: Gioiello, Antimo ; Pellicciari, Roberto ; Ceccarelli, Giada ; Di Bona, Stefano ; Cipolloni, Marco ; Cruciani, Gabriele ; Paccoia, Federico ; Goracci, Laura ; Passeri, Daniela ; Carotti, Andrea

The nuclear receptor ssDAF-12 has been recognized as the key molecular player regulating the life cycle of the nematode parasite Strongyloides stercoralis. ssDAF-12 ligands permit the receptor to function as an on/off switch modulating infection, making it vulnerable to therapeutic intervention. In this study, we report the design and synthesis of a set of novel dafachronic acid derivatives, which were used to outline the first structure-activity relationship targeting the ssDAF-12 receptor and to unveil hidden properties shared by the molecular shape of steroidal ligands that are relevant to the receptor binding and modulation. Moreover, biological results led to the discovery of sulfonamide 3 as a submicromolar ssDAF-12 agonist endowed with a high receptor selectivity, no toxicity, and improved properties, as well as to the identification of unprecedented ssDAF-12 antagonists that can be exploited in the search for novel chemical tools and alternative therapeutic approaches for treating parasitism such as Strongyloidiasis.

14 Feb 2023·ACS Omega

Discovery of a Novel Class of Dual GPBAR1 Agonists–RORγt Inverse Agonists for the Treatment of IL-17-Mediated Disorders

Article

Author: Fiorucci, Stefano ; Fiorillo, Bianca ; di Giorgio, Cristina ; Roselli, Rosalinda ; Biagioli, Michele ; Conflitti, Paolo ; Sepe, Valentina ; Bellini, Rachele ; Limongelli, Vittorio ; Finamore, Claudia ; Cassiano, Chiara ; Zampella, Angela ; Catalanotti, Bruno ; Rapacciuolo, Pasquale ; Marchianò, Silvia ; Bordoni, Martina

Retinoic acid receptor-related orphan receptor γ-t (RORγt) and GPBAR1, a transmembrane G-protein-coupled receptor for bile acids, are attractive drug targets to develop clinically relevant small modulators as potent therapeutics for autoimmune diseases. Herein, we designed, synthesized, and evaluated several new bile acid-derived ligands with potent dual activity. Furthermore, we performed molecular docking and MD calculations of the best dual modulators in the two targets to identify the binding modes as well as to better understand the molecular basis of the inverse agonism of RORγt by bile acid derivatives. Among these compounds, 7 was identified as a GPBAR1 agonist (EC₅₀ 5.9 μM) and RORγt inverse agonist (IC₅₀ 0.107 μM), with excellent pharmacokinetic properties. Finally, the most promising ligand displayed robust anti-inflammatory activity in vitro and in vivo in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.

100 Deals associated with LXR agonists S1(Ocean University of China)

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Preclinical	Netherlands	Erasmus MC	09 Jan 2023
Cardiovascular Diseases	Preclinical	China	Ocean University of China	09 Jan 2023
Neurodegenerative Diseases	Preclinical	Netherlands	Erasmus MC	09 Jan 2023
Neurodegenerative Diseases	Preclinical	China	Ocean University of China	09 Jan 2023

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