Thesis defence
Title :
Designing and enhancing NUPR1 inhibitors for pancreatic cancer treatment
Abstract :
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy for which no effective treatments are available. Our team previously developed a promising candidate, ZZW-115, which has demonstrated excellent anti-PDAC activity by targeting the nuclear protein 1 (NUPR1). NUPR1 is involved in the development and progression of PDAC and represents an excellent target for PDAC treatment. However, the clinical application of ZZW-115 has been impededd due to its potential cardiotoxicity, caused by its binding to the human Ether-à-go-go-Related Gene (hERG) channel. Therefore, this PhD thesis aims to address the hERG-related cardiotoxicity issue of NUPR1 inhibitors in order to improve and enhance their use in PDAC treatment. First, we utilized a nanotechnology-based drug delivery system to deliver ZZW-115 specifically to tumor sites via passive targeting mediated by the enhanced permeability and retention (EPR) effect, thereby avoiding accumulation in heart. In vitro hERG affinity tests also demonstrated that ZZW-115 nanoparticles could reduce hERG affinity of ZZW-115. Additionally, we conducted a high-throughput screening of 10,000 compounds from the HitFinder Chemical Library and identified a novel NUPR1 inhibitor lead, AJO14. A series of AJO14 derivatives were further developed. Among them, LZX-2-73 emerged as the most promising candidate, with good anti-PDAC activity and extremely low hERG affinity, depriving of potential cardiotoxicity. Finally, to enhance the anticancer activity of LZX-2-73, we utilized a combination therapy strategy and discovered that LZX-2-73 exhibited strong synergistic anticancer effects with sorafenib. This combination not only enhanced the anti-PDAC activity of the NUPR1 inhibitor but also expanded the anticancer spectrum of sorafenib. In summary, my PhD research project has elaborated multiple approaches to overcome the hERG-related cardiotoxicity of NUPR1 inhibitors and increase their anti-PDAC efficacy, offering effective treatment options for the lethal PDAC.
Key words : Pancreatic ductal adenocarcinoma, NUPR1, ZZW-115, hERG-related cardiotoxicity, Dendrimer, LZX-2-73, Combination therapy