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

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 (IC ₅₀  = 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 IC ₅₀  = 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cristian O. Salas reports financial support was provided by FONDECYT. Gunnar Schulte and Pawel Kozielewicz reports financial support was provided by The Swedish Research Counsil. Gunnar Schulte and Pawel Kozielewicz reports financial support was provided by The Swedish Cancer Society. Gunnar Schulte and Pawel Kozielewicz reports financial support was provided by The NovoNordisk Foundation. Gunnar Schulte and Pawel Kozielewicz reports financial support was provided by The Lars Hierta Memorial Foundation. Marcelo Kogan reports financial support was provided by FONDAP. Lucia Di Marcotullio reports financial support was provided by Fondazione AIRC. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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