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  3. New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer

New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer

  • Bioorg Chem. 2024 Oct:151:107681. doi: 10.1016/j.bioorg.2024.107681.
Christian Espinosa-Bustos 1,  Jeanluc Bertrand 2,  Alondra Villegas-Menares 2,  Simón Guerrero 3,  Lucia Di Marcotullio 4,  Shirin Navacci 5,  Gunnar Schulte 6,  Pawel Kozielewicz 6,  Nicolas Bloch 2,  Valentina Villela 2,  Margot Paulino 7,  Marcelo J Kogan 8,  Jorge Cantero 7,  Cristian O Salas 9
Affiliations

Affiliations

  • 1 Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile.
  • 2 Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile.
  • 3 Facultad de Medicina, Universidad de Atacama, 153601 Copiapó, Chile.
  • 4 Department of Molecular Medicine, Faculty Pharmacy and Medicine, Sapienza University, 00161 Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University, 00161 Rome, Italy.
  • 5 Department of Molecular Medicine, Faculty Pharmacy and Medicine, Sapienza University, 00161 Rome, Italy.
  • 6 Department of Physiology and Pharmacology, Karolinska Institute, 17165 Solna, Stockholm, Sweden.
  • 7 Departamento DETEMA, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay.
  • 8 Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, 8380492 Santiago, Chile; Advanced Center of Chronic Diseases (ACCDiS), Universidad de Chile, 8380492 Santiago, Chile.
  • 9 Departamento de Química Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile. Electronic address: cosalas@uc.cl.
PMID: 39106711 DOI: 10.1016/j.bioorg.2024.107681
Abstract

Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic Cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G protein-coupled receptor Smoothened (Smo) has been considered as a therapeutic target for the treatment of this Cancer. In our previous work, we obtained a new Smo ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several Cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic Cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 μM, respectively). Two of these purines also showed their ability to bind to Smo through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on Smo. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced Gli activity with a IC50 = 6.4 μM as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1-/- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of Smo ligands that could be potential selective cytotoxic agents for the treatment of pancreatic Cancer.

Keywords

Cytotoxicity; Docking studies; NanoBRET; Pancreatic cancer; Purine derivatives; SMO ligands.

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