Abstract B030: The quadruplex-binding compound QN-302 targets the S100P gene in PDAC

Abstract

Abstract The compound QN-302, a tetra-substituted naphthalene diimide derivative has been previously disclosed to have single-digit nM anti-proliferative activity in a panel of human pancreatic ductal adenocarcinoma (PDAC) cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It also has significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC as well as in the more demanding KPC model. Its novel mode of action involves the targeting of quadruplex (G4)-forming motifs in promoter regions of cancer-associated genes, where their prevalence is over-represented compared to other genes. The presence of a promoter G4 motif, stabilized by a ligand, presents an effective block to transcription. Transcriptome analyses of QN-302 in MIA-PACA2 cells has validated this concept, with the disclosure of a pattern of down-regulated genes involved in cancer-associated pathways and carrying G4 motifs in their promoters. We have also previously shown using RT-PCR and Western blots that a sub-set of these genes and their gene products are down-regulated in the MIA-PACA2 xenograft model following QN-302 treatment. We have now examined cellular changes in the expression of the 229 gene set associated with PDAC and compared these with data from cells and xenografts treated with QN-302. We find that expression of the key gene S100P, a prominent and well-authenticated marker of PDAC disease and progression, is highly down-regulated in QN-302 treated cells. The S100P gene contains 31 putative G4 motifs, including a classic G4 site in the S100P promoter, just upstream of the transcription start site. Transcriptome analyses have also been performed on tumor material from human patients, comprising a panel of poorly differentiated as well as more highly differentiated tumors, and has been compared with normal pancreas expression data. The S100P gene is statistically significantly highly over-expressed (especially in the poorly differentiated tumors), giving added confidence to the concept that the S100P gene is a therapeutic target and may also be useful as a marker of QN-302 response in future clinical use. We also find that the anti-tumor effect of QN-302 treatment in PDAC xenografts results in a high level of apoptosis, which is consistent with earlier reports that S100P in tumors binds to and suppresses p53 activity. The suppression of S100P transcription by QN-302 would thus be expected to remove this roadblock to apoptosis and cell death, in accordance with our observations. QN-302 is bio-available at therapeutic doses and is well tolerated at these levels in these animal models. It is being developed for clinical evaluation by Qualigen Therapeutics Inc and is currently at the pre-IND stage. Citation Format: Ahmed Ahmed, William Greenhalf, Tariq Arshad, Stephen S. Neidle. The quadruplex-binding compound QN-302 targets the S100P gene in PDAC [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 B030.