Abstract A079: The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses

Abstract

Abstract The human genome contains multiple sites of quadruplex (G4) arrangements, with over-representation in promoter regions of many oncogenes. Small molecule G4 stabilization down-regulates the transcription of these genes, leading to selective inhibition of cancer cell growth and anti-tumor activity. We have developed a number of novel G4-binding small molecules. QN-302, the most potent, has significant in vivo activity in animal models for pancreatic cancer and is currently in pre-clinical development with Qualigen Therapeutics. The effects of QN-302 have been examined on (1) a panel of cardiac function receptors, (2) heart rate in vivo, and (3) on the histopathology of organs from treated animals. QN-302 was initially screened in a series of in vitro industry-standard CEREP receptor binding assays. The few apparent indications of significant receptor binding were examined in vivo by means of ELISA assays. Cardiac function was examined using a cardiac heart-beat monitor attached to animals treated with QN-302 and compared to animals dosed with a vehicle control. QN-302 gave negative results in CEREP assays, apart from micromolar inhibition of acetylcholinesterase (ACE) and muscarinic (MUSC) receptors. There was no significant hERG receptor inhibition. There was no significant inhibition of ACE and MUSC receptors in vivo. Heart rate experiments, run at both the proposed therapeutic dose of 1mg/kg and at elevated levels, did not show significant deviations from values for the vehicle control arm. Histopathology of heart, liver and brain tissues from QN-302 treated animals, did not show any deleterious effects from the drug. The lack of effects on ACE and MUSC receptors in vivo, together with the absence of effects on heart, liver and brain tissue from treated animals and the normality of heart rate during treatment, demonstrate that treatment of MIA-Paca2 tumor-bearing mice with QN-302 does not have a cardio-, nephro- or neurotoxic burden at therapeutic doses. QN-302 is bio-available at therapeutic doses and is currently in pre-clinical development with Qualigen Therapeutics Inc Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The quadruplex-binding compound QN-302 in the MIA-PaCa2 pancreatic adenocarcinoma model shows no evidence of cardiac or neurological liabilities at therapeutic doses [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 A079.