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

## TL;DR

This study introduces new para-phenylenediamine-based compounds that inhibit ROR1, a promising cancer target, showing strong anticancer potential in lab tests.

## Contribution

The paper presents novel para-phenylenediamine derivatives as effective ROR1 inhibitors with demonstrated anticancer activity.

## Key findings

- Compound 17 shows strong affinity for ROR1 and inhibits its protumoral activity in cancer cell lines.
- Pharmacokinetic tests reveal good stability for derivative 17, supporting further development.
- The study confirms the potential of para-phenylenediamine as a scaffold for ROR1 inhibitors.

## 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, 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.

ROR1 represents a promising target for the development of novel antiproliferative compounds, giving its high expression in different cancer cell lines. The present study describes the workflow leading to the design, synthesis, and characterization of a series of para‐phenylenediamine‐based compounds able to interact with the target kinase, inhibiting its pro‐tumor effect.© 2025 WILEY‐VCH GmbH