CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and aurora A

Cazares-Körner, Cindy; Pires, Isabel M.; Swallow, I. Diane; Grayer, Samuel C.; O'Connor, Liam J.; Olcina, Monica M.; Christlieb, Martin; Conway, Stuart J.; Hammond, Ester M.

Abstract

The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability. © 2013 American Chemical Society.

Citation

Cazares-Körner, C., Pires, I. M., Swallow, I. D., Grayer, S. C., O'Connor, L. J., Olcina, M. M., …Hammond, E. M. (2013). CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and aurora A. ACS Chemical Biology, 8(7), 1451-1459. https://doi.org/10.1021/cb4001537

• Acceptance Date: Apr 18, 2013
• Online Publication Date: Apr 18, 2013
• Publication Date: Jul 19, 2013
• Deposit Date: Mar 21, 2018
• Publicly Available Date: May 3, 2018
• Journal: ACS Chemical Biology
• Print ISSN: 1554-8929
• Electronic ISSN: 1554-8937
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 7
• Pages: 1451-1459
• DOI: https://doi.org/10.1021/cb4001537
• Keywords: Molecular Medicine; Biochemistry; General Medicine
• Public URL: https://hull-repository.worktribe.com/output/749201
• Publisher URL: https://pubs.acs.org/doi/10.1021/cb4001537