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

被引：0

作者：

Smaldone, Gerardina ^{[1
]}

Miranda, Maria Rosaria ^{[1
]}

Di Matteo, Francesca ^{[1
]}

Napolitano, Valeria ^{[1
]}

Aliberti, Michela ^{[1
]}

Musella, Simona ^{[1
]}

Di Sarno, Veronica ^{[1
]}

Lauro, Gianluigi ^{[1
]}

Bifulco, Giuseppe ^{[1
]}

Pepe, Giacomo ^{[1
]}

Aquino, Giovanna ^{[1
]}

Tecce, Mario Felice ^{[1
]}

Gomez-Monterrey, Isabel Maria ^{[2
]}

Campiglia, Pietro ^{[1
]}

Ostacolo, Carmine ^{[1
]}

Bertamino, Alessia ^{[1
]}

Vestuto, Vincenzo ^{[1
]}

Ciaglia, Tania ^{[1
]}

机构：

[1] Univ Salerno, Dept Pharm, Via G Paolo II 132, I-84084 Salerno, Italy

[2] Univ Federico II Naples, Dept Pharm, Via D Montesano 49, I-80131 Naples, Italy

来源：

CHEMMEDCHEM | 2025年 / 20卷 / 14期

关键词：

binding assays; cytotoxic effects; kinase inhibitors; novel chemotypes; synthesis; ACCURATE DOCKING; PSEUDOKINASE; PROTEIN; GLIDE; TARGET;

D O I：

10.1002/cmdc.202500247

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：15

共 46 条

[1]

Allegra M., 2020, BIOMOLECULES, V10, 994

[2]

[Anonymous], 2021, SCHRDINGER RELEASE 2

[3]

Arias A. M., 2006, PLOS BIOL, V4

[4] Unique cell surface expression of receptor tyrosine kinase ROR1 in human B-cell chronic lymphocytic leukemia [J].