Synthesis and biological evaluation of a new class of azole urea compounds as Akt inhibitors with promising anticancer activity in pancreatic cancer models
- Bioorg Chem. 2024 Dec:153:107959. doi: 10.1016/j.bioorg.2024.107959.
- 1. Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.
- 2. Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam 1081 HV, The Netherlands.
- 3. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam 1081 HV, The Netherlands.
- 4. Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: [email protected].
- 5. Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam 1081 HV, The Netherlands; Cancer Pharmacology Laboratory, Fondazione Pisana per la Scienza, Via Ferruccio Giovannini 13, 56017 Pisa, Italy. Electronic address: [email protected].
The PI3K/Akt pathway is crucial in numerous cellular functions such as cell growth, survival proliferation and movement in both normal and Cancer cells. It plays also a key role in epithelial-mesenchymal transitions and angiogenesis during the tumorigenesis processes. Since many transformative events in Cancer are driven by increased PI3K/Akt pathway signaling, Akt is considered a valuable target for developing new therapies against various tumor types, including pancreatic Cancer. This is because the PI3K/Akt/mTOR pathway is a key downstream effector of Ras, and Ras activation is the most prominent genetic alteration in pancreatic Cancer. Herein we report the synthesis and the biological evaluation of a new series of azole urea compounds that exhibited promising antiproliferative and antimigratory activities against pancreatic Cancer cells through an Akt inhibition mechanism. These effects were demonstrated using a variety of assays, including Sulforhodamine B, cell-cycle, wound-healing, and kinase activity, apotposis and ELISA assays. Additionally, the Anticancer properties of the most active compound in the series were confirmed in the 3D spheroid model of PATU-T cells.