Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure-based molecular modification.
Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Haopeng
H
Sun
Xiaoli
X
Xu
Xiaowen
X
Wu
Xiaojin
X
Zhang
Fang
F
Liu
Jianmin
J
Jia
Xiaoke
X
Guo
Jingjie
J
Huang
Zhengyu
Z
Jiang
Taotao
T
Feng
Hongxi
H
Chu
You
Y
Zhou
Shenglie
S
Zhang
Zongliang
Z
Liu
Qidong
Q
You
D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D010619:Phenazines; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D012984:Software; D014584:User-Computer Interface
D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; C555142:silmitasertib; D047390:Casein Kinase II