: ROR1 kinase is an underexplored promising target for the development of novel anticancer drugs, being strongly expressed in several cancer cell lines, but poorly in non-tumor cells. This property, together with the scarce number of molecules effective against ROR1, led us to design and develop a research program aimed to the discovery of new chemical entities able to inhibit ROR1 thus interfering with its pro-tumoral activity. Step-by-step in silico studies guided the design and synthesis of para-phenylenediamine-based compounds. SPR and CETSA analyses, coordinated with cytotoxicity assays carried out on JeKo-1 (mantle cell lymphoma) and SH-SY5Y (neuroblastoma cell) cell lines, demonstrated the strong affinity and the anticancer potential of the derivative 17, respectively, further confirming its mechanism of action. Moreover, pharmacokinetic assessment revealed a good stability profile for derivative 17, paving the way for additional SAR studies on the para-phenylenediamine as a scaffold for developing new ROR1 inhibitors.
Novel para‐phenylenediamine‐based derivatives as Receptor Tyrosine Kinase‐like Orphan Receptor 1 (ROR1) Inhibitors: An in vitro preliminary characterization
Smaldone, Gerardina;Miranda, Maria Rosaria;Di Matteo, Francesca;Napolitano, Valeria;Aliberti, Michela;Musella, Simona;Di Sarno, Veronica;Lauro, Gianluigi;Bifulco, Giuseppe;Pepe, Giacomo;Aquino, Giovanna;Tecce, Mario Felice;Campiglia, Pietro;Ostacolo, Carmine;Bertamino, Alessia;Vestuto, Vincenzo
;CIAGLIA, Tania
2025
Abstract
: ROR1 kinase is an underexplored promising target for the development of novel anticancer drugs, being strongly expressed in several cancer cell lines, but poorly in non-tumor cells. This property, together with the scarce number of molecules effective against ROR1, led us to design and develop a research program aimed to the discovery of new chemical entities able to inhibit ROR1 thus interfering with its pro-tumoral activity. Step-by-step in silico studies guided the design and synthesis of para-phenylenediamine-based compounds. SPR and CETSA analyses, coordinated with cytotoxicity assays carried out on JeKo-1 (mantle cell lymphoma) and SH-SY5Y (neuroblastoma cell) cell lines, demonstrated the strong affinity and the anticancer potential of the derivative 17, respectively, further confirming its mechanism of action. Moreover, pharmacokinetic assessment revealed a good stability profile for derivative 17, paving the way for additional SAR studies on the para-phenylenediamine as a scaffold for developing new ROR1 inhibitors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
