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

• Published in: Bioorganic chemistry Vol. 151; p. 107681
• Main Authors: Espinosa-Bustos, Christian, Bertrand, Jeanluc, Villegas-Menares, Alondra, Guerrero, Simón, Di Marcotullio, Lucia, Navacci, Shirin, Schulte, Gunnar, Kozielewicz, Pawel, Bloch, Nicolas, Villela, Valentina, Paulino, Margot, Kogan, Marcelo J., Cantero, Jorge, Salas, Cristian O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2024
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cytotoxicity; Docking studies; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; HEK293 Cells; Humans; Ligands; Medicin och hälsovetenskap; Mice; Molecular Docking Simulation; Molecular Structure; NanoBRET; NIH 3T3 Cells; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Purine derivatives; Purines - chemical synthesis; Purines - chemistry; Purines - pharmacology; SMO ligands; Smoothened Receptor - antagonists & inhibitors; Smoothened Receptor - metabolism; Structure-Activity Relationship; Docking studies; Cytotoxicity; Purine derivatives; NanoBRET; SMO ligands; Pancreatic cancer
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107681

[Display omitted] •Design and synthesis of new 2,6,9-trisubstituted purine derivatives.•8f, 8g and 8h have IC50 values of 4.56, 4.11 and 3.08 μM on Mia-PaCa-2 cells, respectively.•8f and 8h bind to SMO with higher affinities that our previous SMO ligand.•8g was able to inhibit Hh pathway on luciferase activity in NIH3T3 Shh-Light II cells.•8g diminished the expression of Hh signalling target genes. 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.