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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.

Authors

Cindy Cazares-Körner

I. Diane Swallow

Samuel C. Grayer

Liam J. O'Connor

Monica M. Olcina

Martin Christlieb

Stuart J. Conway

Ester M. Hammond



Contributors

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.

Publication Date Jul 19, 2013
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
Institution 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
DOI https://doi.org/10.1021/cb4001537
Keywords Molecular Medicine; Biochemistry; General Medicine
Publisher URL https://pubs.acs.org/doi/10.1021/cb4001537
Copyright Statement © 2013 American Chemical Society

ACS AuthorChoice - Terms of Use

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Copyright Statement
© 2013 American Chemical Society

ACS AuthorChoice - Terms of Use



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