Structure-activity relationship study of 4-(thiazol-5-yl)benzoic acid derivatives as potent protein kinase CK2 inhibitors

  • Bioorg Med Chem. 2016 Mar 1;24(5):1136-41. doi: 10.1016/j.bmc.2016.01.043.
Hiroaki Ohno  1 ,  Daiki Minamiguchi  2 ,  Shinya Nakamura  3 ,  Keito Shu  2 ,  Shiho Okazaki  2 ,  Maho Honda  2 ,  Ryosuke Misu  2 ,  Hirotomo Moriwaki  3 ,  Shinsuke Nakanishi  3 ,  Shinya Oishi  2 ,  Takayoshi Kinoshita  4 ,  Isao Nakanishi  3 ,  Nobutaka Fujii  5
Affiliations
  • 1. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: [email protected].
  • 2. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 3. Faculty of Pharmacy, Department of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.
  • 4. Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
  • 5. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: [email protected].
PMID: 26850376 DOI: 10.1016/j.bmc.2016.01.043
Abstract

Two classes of modified analogs of 4-(thiazol-5-yl)benzoic acid-type CK2 inhibitors were designed. The azabenzene analogs, pyridine- and pyridazine-carboxylic acid derivatives, showed potent protein kinase CK2 inhibitory activities [IC50 (CK2α)=0.014-0.017μM; IC50 (CK2α')=0.0046-0.010μM]. Introduction of a 2-halo- or 2-methoxy-benzyloxy group at the 3-position of the benzoic acid moiety maintained the potent CK2 inhibitory activities [IC50 (CK2α)=0.014-0.016μM; IC50 (CK2α')=0.0088-0.014μM] and led to antiproliferative activities [CC50 (A549)=1.5-3.3μM] three to six times higher than those of the parent compound.

Keywords
Kinase inhibitor; Protein kinase CK2; Rational design; Structure–activity relationship.