2. Academic Validation
  3. Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line

Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line

  • Eur J Med Chem. 2024 Jul 15:276:116681. doi: 10.1016/j.ejmech.2024.116681.
Lorenzo Guidetti 1,  Riccardo Castelli 1,  Alfonso Zappia 1,  Francesca Romana Ferrari 1,  Carmine Giorgio 1,  Elisabetta Barocelli 1,  Luca Pagliaro 2,  Federica Vento 3,  Giovanni Roti 2,  Laura Scalvini 1,  Federica Vacondio 1,  Silvia Rivara 1,  Marco Mor 4,  Alessio Lodola 5,  Massimiliano Tognolini 6
Affiliations

Affiliations

  • 1 Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parma, Italy.
  • 2 Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy; Ematologia e CTMO, Azienda Ospedaliero Universitaria di Parma, Parma, Italy; Translational Hematology and Chemogenomics (THEC), Università di Parma, Parma, Italy.
  • 3 Translational Hematology and Chemogenomics (THEC), Università di Parma, Parma, Italy; Dipartimento di Scienze Mediche, Università di Ferrara, Ferrara, Italy.
  • 4 Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parma, Italy; Microbiome Research Hub, Università di Parma, Parma, Italy.
  • 5 Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parma, Italy. Electronic address: alessio.lodola@unipr.it.
  • 6 Dipartimento di Scienze degli Alimenti e del Farmaco, Università di Parma, Parma, Italy. Electronic address: massimiliano.tognolini@unipr.it.
PMID: 39024966 DOI: 10.1016/j.ejmech.2024.116681
Abstract

In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-β-homotryptophan conjugates of 3-β-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit Ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.

Keywords

Docking; EphA2; Glioblastoma; Protein-protein interaction; SAR.

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