Novel Para-Phenylenediamine-Based Derivatives as Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Inhibitors: An In Vitro Preliminary Characterization

: 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, 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-by-step in silico studies guide the design and synthesis of para-phenylenediamine-based compounds. Surface plasmon resonance and Cellular Thermal Shift Assay analyses, coordinated with cytotoxicity assays carried out on JeKo-1 (mantle cell lymphoma) and SH-SY5Y (neuroblastoma cell) cell lines, demonstrate the strong affinity and the anticancer potential of the derivative 17, respectively, further confirming its mechanism of action. Moreover, pharmacokinetic assessment reveals 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.