Abstract
Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across cancer types, and this presents metal chelation as an attractive cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular reactive oxygen species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive cancer stem cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets cancer cells with increased mitochondrial function. Furthermore, patient-derived organoid models demonstrate that KS10076 efficiently represses cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.
| Original language | English |
|---|---|
| Article number | 111077 |
| Journal | Cell Reports |
| Volume | 40 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2022 Jul 19 |
Bibliographical note
Funding Information:We are grateful to all of the supporting faculty, staff, and colleagues. We appreciate Dr. Doo-Young Jung (PinotBIO). We thank Hongjeong Yoon and Choong-kun Lee for the invaluable support and intellectual contributions. In addition, we thank Dr. Dongwook Kim (IBS, Korea) for helpful discussion and experimental support for single X-ray crystallographic analysis. This research was supported by PinotBIO ( IIT21-23 ).
Funding Information:
H.L. and S.J.S. report research funding from PinotBIO. A.P., J.K., H.L., and S.J.S. have a patent of KS10076.
Publisher Copyright:
© 2022 The Author(s)
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
