Design, synthesis, and biological activity of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one-based potent and selective Chk-1 inhibitors.
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.
R47B, Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. le.wang@abbott.com
Le
L
Wang
Gerard M
GM
Sullivan
Laura A
LA
Hexamer
Lisa A
LA
Hasvold
Reema
R
Thalji
Magdalena
M
Przytulinska
Zhi-Fu
ZF
Tao
Gaoquan
G
Li
Zehan
Z
Chen
Zhan
Z
Xiao
Wen-Zhen
WZ
Gu
John
J
Xue
Mai-Ha
MH
Bui
Philip
P
Merta
Peter
P
Kovar
Jennifer J
JJ
Bouska
Haiying
H
Zhang
Chang
C
Park
Kent D
KD
Stewart
Hing L
HL
Sham
Thomas J
TJ
Sowin
Saul H
SH
Rosenberg
Nan-Horng
NH
Lin
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
C523821:2-(3-(3-methoxy-4-nitrophenyl)-11-oxo-10,11-dihydro-5H-dibenzo(b,e)(1,4)diazepin-8-yl)-N,N-dimethylacetamide; D000970:Antineoplastic Agents; D001381:Azepines; D001570:Benzodiazepinones; D047428:Protein Kinase Inhibitors; D004317:Doxorubicin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D002166:Camptothecin