Abstract B051: Design, synthesis, and in vitro evaluation of enedione derivatives as promising selective COPZ1 inhibitor

Abstract

Abstract Pancreatic cancer is a disease with a rising incidence and low survival rate. Anticancer drugs are effective, but are not selective, leading to serious side effects, as pain, loss of taste bud, and hair loss. The available treatments are involved in target cell proliferation, but are ineffective against nonproliferating tumor cells, which could lead to a relapse. COPZ1 and its paralogous COPZ2 are involved in intracellular trafficking and autophagy. They were identified as essential for healthy and tumor cell survival. Both COPZ1 and COPZ2 are expressed in almost the same level in normal cells. Interestingly, in tumor cells, COPZ2 is downregulated. In normal cells, the simultaneous depletion of both COPZ1 and COPZ2 leads normal cells to apoptosis, but the depletion of only one of the proteins does not affect cell cycle. This fact led us to the hypothesis that tumor cells are COPZ1 dependent, and the inhibition of this protein could lead tumor cells to apoptosis selectively once COPZ2 is naturally downregulated. Once these proteins are involved in intracellular trafficking, the inhibition of COPZ1 in COPZ2-defficient tumor cells could cause Golgi apparatus collapse, block autophagy, and induce apoptosis in both proliferating and dormant cells. This suggests that the COPZ1 knockdown may suppress tumor growth selectively, making it a promising cancer therapy target. We used molecular docking, synthesis and cell biology to prove our hypothesis. To obtain the 3D structure of COPZ2 for in silico studies purpose, a homology modeling was performed using the amino acids sequence. A set of 84 molecules were submitted to molecular docking, and 4 compounds containing the active metabolite 4-aminoantipyrine and enedione fragment were selected for synthesis and in vitro evaluation. The selection was based on the interactions between the inhibitor and the amino acids within the binding site of the enzyme. Interestingly, the selected 1-4 compounds showed cellular growth inhibition of MIA PaCa-2 and AsPC-1 cell lines, but not for normal cell line. Our new drug prototypes based on 4-aminoantipyrine and enedione moieties showed quite good anti-cancer properties, therefore deserving to be considered in further studies with the aim of understanding the role of COPZ1 in tumor development, as a target for selective treatment. Citation Format: Allana Cristina F. Martins, Barbara M. Barbosa, Bretton Badenoch, Roberto S. Gomes. Design, synthesis, and in vitro evaluation of enedione derivatives as promising selective COPZ1 inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B051.