Design and Synthesis of Novel Reactive Oxygen Species Inducers for the Treatment of Pancreatic Ductal Adenocarcinoma

Altering redox homeostasis provides
distinctive therapeutic opportunities
for the treatment of pancreatic cancer. Quinazolinediones (QDs) are
novel redox modulators that we previously showed to induce potent
growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell
lines. Our lead optimization campaign yielded QD325 as
the most potent redox modulator candidate inducing substantial reactive
oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following
treatments with the QD compounds revealed induction of stress responses
in nucleus, endoplasmic reticulum, and mitochondria of pancreatic
cancer cells. Furthermore, the QD compounds induced Nrf2-mediated
oxidative stress and unfolded protein responses as demonstrated by
dose-dependent increases in RNA synthesis of representative genes
such as NQO1, HMOX1, DDIT3, and HSPA5. At higher concentrations, the QDs blocked mitochondrial function
by inhibiting mtDNA transcription and downregulating the mtDNA-encoded
OXPHOS enzymes. Importantly, treatments with QD325 were
well tolerated in vivo and significantly delayed
tumor growth in mice. Our study supports the development of QD325 as a new therapeutic in the treatment of PDAC.