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This property, together with the scarce number of molecules effective against ROR1, leads to the design and development of a research program aimed at the discovery of new chemical entities able to inhibit ROR1 thus interfering with its protumoral activity. Step\u2010by\u2010step in silico studies guide the design and synthesis of <jats:italic>para<\/jats:italic>\u2010phenylenediamine\u2010based compounds. Surface plasmon resonance and Cellular Thermal Shift Assay analyses, coordinated with cytotoxicity assays carried out on JeKo\u20101 (mantle cell lymphoma) and SH\u2010SY5Y (neuroblastoma cell) cell lines, demonstrate the strong affinity and the anticancer potential of the derivative <jats:bold>17<\/jats:bold>, respectively, further confirming its mechanism of action. 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