Substituted bithiazoles for safer combinational chemotherapy treatments
Cancer remains one of the most widespread and deadly diseases, with nearly 10 million deaths and 20 million new cases reported annually by the WHO. A key target in cancer treatment is DNA topoisomerase IIα, an enzyme critical for managing DNA topology during cell replication. However, current topo II inhibitors, known as topo II poisons, are linked to severe side effects, including cardiotoxicity and secondary cancers, due to their tendency to induce double-strand breaks (DSBs) in DNA, which complicates treatment and limits therapeutic use.
A class of substituted 4,5'-bithiazoles, unlike conventional topoisomerase II poisons, inhibits human topoisomerase IIα through an alternative ATP-competitive mechanism. These compounds retain cancer cytotoxicity levels comparable to clinical topo II poisons but avoid inducing double-strand breaks (DSBs), potentially reducing harmful side effects. In vivo studies show that bithiazoles exhibit a favorable safety profile, both as monotherapy and in combination with topo II poisons. Efficacy studies demonstrate that bithiazoles reduce tumor growth in mouse models and enhance therapeutic outcomes when combined with topo II poisons.
Bithiazoles can be incorporated into current chemotherapy regimens, alongside established anticancer agents such as topoisomerase II poisons, type I topoisomerase inhibitors, and protein kinase inhibitors, to enhance therapeutic efficacy. This approach positions bithiazoles as a next-generation solution for combination chemotherapy, potentially improving patient outcomes.
Developed by: Theory Department.
Technology readiness level: TRL3–4.
Status of intellectual property:Patent granted.
Cooperation opportunities: Joint development, intellectual property licensing, or sale.
2023 NICKI Support Recipient
Scientific and academic papers
Bergant Loboda, K., Janežič, M., Štampar, M., Žegura, B., Filipič, M., Perdih, A. (2020). Substituted 4,5'-Bithiazoles as Catalytic Inhibitors of Human DNA Topoisomerase IIα. J Chem Inf Model. 2020 Jul 27;60(7):3662-3678. https://doi.org/10.1021/acs.jcim.0c00202.