Novel para‐phenylenediamine‐based derivatives as Receptor Tyrosine Kinase‐like Orphan Receptor 1 (ROR1) Inhibitors: An in vitro preliminary characterization

• DOI: 10.1002/cmdc.202500247
• Publication Date: 2025-05-07T02:24:55Z
• Authors: Gerardina Smaldone; Maria Rosaria Mir...; Francesca Di Matteo; Valeria Napolitano; Michela Aliberti; Simona Musella; Veronica Di Sarno; Gianluigi Lauro; Giuseppe Bifulco; Giacomo Pepe; Giovanna Aquino; Mario Felice Tecce; Isabel Maria Gome...; Pietro Campiglia; Carmine Ostacolo; Alessia Bertamino; Vincenzo Vestuto; Tania CIAGLIA

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.