Molecule inducers of reactive oxygen species and inhibitors of mitochondrial activity
This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinazolinedione (QD) structure which function as inhibitors of mitochondrial activity within cancer cells (e.g., pancreatic cancer cells), and their use as therapeutics for the treatment of cancer (e.g., pancreatic cancer) and other diseases.
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 some QD compounds 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 QDs were well tolerated in vivo and significantly delayed tumor growth in mice. Our study supports the development of QDs as a new therapeutic in the treatment of PDAC.
- Cancer treatment (e.g. pancreatic cancer and/or PDAC);
- QD compounds function as inhibitors of mitochondrial activity, and serve as therapeutics for the treatment of cancer (e.g., PDAC) and other diseases;
- Mono- and/or combination anticancer therapy.
- Antitumor agents to fight pancreatic cancer and/or PDAC with novel mechanism of action (i.e. ROS dependent anticancer activity – targeting mitochondria);
- Significant antitumor efficacy and favorable safety profile of QDs in vivo.