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Cited by 296

The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.

Discovery and SAR of 5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic Acid (CX-4945), the First Clinical Stage Inhibitor of Protein Kinase CK2 for the Treatment of Cancer

Open access
Pierre, Fabrice, Chua, Peter C., O’Brien, Sean E., Siddiqui-Jain, Adam, Bourbon, Pauline, Haddach, Mustapha, Michaux, Jerome, Nagasawa, Johnny, Schwaebe, Michael K., Stefan, Eric, Vialettes, Anne, Whitten, Jeffrey P., Chen, Ta Kung, Darjania, Levan, Stansfield, Ryan, Anderes, Kenna, Bliesath, Josh, Drygin, Denis, Ho, Caroline, Omori, May, Proffitt, Chris, Streiner, Nicole, Trent, Katy, Rice, William G., Ryckman, David M.·2011·Journal of Medicinal Chemistry
DOI 10.1021/jm101251q
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Abstract

Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2's small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (K(i) = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.

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Metadata

Authors
Pierre, F., Chua, P. C., O’Brien, S. E., Siddiqui-Jain, A., Bourbon, P., Haddach, M., Michaux, J., Nagasawa, J., Schwaebe, M. K., Stefan, E., Vialettes, A., Whitten, J. P., Chen, T. K., Darjania, L., Stansfield, R., Anderes, K., Bliesath, J., Drygin, D., Ho, C., Omori, M., Proffitt, C., Streiner, N., Trent, K., Rice, W. G., & Ryckman, D. M.
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2010-12-21
Volume
54
Issue
2
Pages
635-654
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/jm101251q
OpenAlex
W2033433713
Cited by
296
References
32
FWCI
10.58
Type
journal article
Language
en
Open access
green

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