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.
Nie
Zhe
Z
Department of Medicinal Chemistry, Polaris Pharmaceuticals Inc., San Diego, CA 92121, USA. zhe.nie@takedasd.com
Perretta
Carin
C
Erickson
Philip
P
Margosiak
Stephen
S
Lu
Jia
J
Averill
April
A
Almassy
Robert
R
Chu
Shaosong
S
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