Novel, potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles.
The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.
Engler
Thomas A
TA
Lilly Research Laboratories, Eli Lilly and Company, 46285, Indianapolis, IN, USA. engler_thomas@lilly.com
Furness
Kelly
K
Malhotra
Sushant
S
Sanchez-Martinez
Concha
C
Shih
Chuan
C
Xie
Walter
W
Zhu
Guoxin
G
Zhou
Xun
X
Conner
Scott
S
Faul
Margaret M
MM
Sullivan
Kevin A
KA
Kolis
Stanley P
SP
Brooks
Harold B
HB
Patel
Bharvin
B
Schultz
Richard M
RM
DeHahn
Tammy B
TB
Kirmani
Kashif
K
Spencer
Charles D
CD
Watkins
Scott A
SA
Considine
Eileen L
EL
Dempsey
Jack A
JA
Ogg
Catherine A
CA
Stamm
Nancy B
NB
Anderson
Bryan D
BD
Campbell
Robert M
RM
Vasudevan
Vasu
V
Lytle
Michelle L
ML
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D012413:Rubidium / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D012413:Rubidium