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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
- Source :
- Journal of medicinal chemistry. 54(2)
- Publication Year :
- 2010
-
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.
- Subjects :
- Models, Molecular
Molecular model
Carboxylic acid
Transplantation, Heterologous
Biological Availability
Mice, Nude
Antineoplastic Agents
Pharmacology
Therapeutic targeting
Binding, Competitive
Hydrophobic effect
Mice
Structure-Activity Relationship
Adenosine Triphosphate
Dogs
Biological property
Protein kinase CK2
Cell Line, Tumor
Drug Discovery
medicine
Animals
Humans
Binding site
Naphthyridines
Casein Kinase II
chemistry.chemical_classification
Mice, Inbred ICR
Cancer
Hydrogen Bonding
medicine.disease
Rats
chemistry
Molecular Medicine
Phenazines
Drug Screening Assays, Antitumor
Hydrophobic and Hydrophilic Interactions
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 54
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....381f31afdb18ac8eca61f6768c660619