Download MendeleyStructure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo.
Dowling, J.E., Alimzhanov, M., Bao, L., Block, M.H., Chuaqui, C., Cooke, E.L., Denz, C.R., Hird, A., Huang, S., Larsen, N.A., Peng, B., Pontz, T.W., Rivard-Costa, C., Saeh, J.C., Thakur, K., Ye, Q., Zhang, T., Lyne, P.D.(2013) ACS Med Chem Lett 4: 800-805
- PubMed: 24900749
- DOI: https://doi.org/10.1021/ml400197u
- Primary Citation of Related Structures:
4GRB - PubMed Abstract:
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.
Organizational Affiliation:
AstraZeneca , Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
