Structure-based design and synthesis of novel macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities.
A series of macrocyclic derivatives has been designed and synthesized based on the X-ray co-crystal structures of pyrazolo[1,5-a] [1,3,5]triazines with corn CK2 (cCK2) protein. Bioassays demonstrated that these macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds are potent CK2 inhibitors with K(i) around 1.0 nM and strongly inhibit cancer cell growth with IC(50) as low as approximately 100 nM.
Department of Medicinal Chemistry, Polaris Pharmaceuticals Inc., San Diego, CA 92121, USA. zhe.nie@takedasd.com
Zhe
Z
Nie
Carin
C
Perretta
Philip
P
Erickson
Stephen
S
Margosiak
Jia
J
Lu
April
A
Averill
Robert
R
Almassy
Shaosong
S
Chu
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D011471:Prostatic Neoplasms / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014227:Triazines; D047390:Casein Kinase II