Novel <i>Para</i>‐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.
Authors
- Tania Ciaglia (ORCID: https://orcid.org/0000-0002-6592-4373)
- Mario Felice Tecce (ORCID: https://orcid.org/0000-0003-2355-6047)
- Giovanna Aquino (ORCID: https://orcid.org/0000-0001-5457-1712)
- Carmine Ostacolo (ORCID: https://orcid.org/0000-0003-3715-8680)
- Francesca Di Matteo (ORCID: https://orcid.org/0000-0002-9907-6472)
- Veronica Di Sarno (ORCID: https://orcid.org/0000-0002-1397-5240)
- Giuseppe Bifulco (ORCID: https://orcid.org/0000-0002-1788-5170)
- Vincenzo Vestuto (ORCID: https://orcid.org/0000-0002-3603-5526)
- Simona Musella (ORCID: https://orcid.org/0000-0001-8312-4241)
- Isabel Gómez‐Monterrey (ORCID: https://orcid.org/0000-0001-6688-2606)
- Giacomo Pepe (ORCID: https://orcid.org/0000-0002-7561-2023)
- Gerardina Smaldone (ORCID: https://orcid.org/0000-0003-1380-9717)
- Alessia Bertamino (ORCID: https://orcid.org/0000-0002-5482-6276)
- Pietro Campiglia (ORCID: https://orcid.org/0000-0002-1069-2181)
- Gianluigi Lauro (ORCID: https://orcid.org/0000-0001-5065-9717)
- Valeria Napolitano (ORCID: https://orcid.org/0000-0003-2328-2824)
- Maria Rosaria Miranda (ORCID: https://orcid.org/0009-0005-8296-1888)
- Michela Aliberti
Institutions
- University of Salerno (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- ChemMedChem
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1002/cmdc.202500247
- Primary Topic
- Nuclear Receptors and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00