Aryl[a]pyrrolo[3,4-c]carbazoles as selective cyclin D1-CDK4 inhibitors.
The synthesis of new analogues of Arcyriaflavin A in which one indole ring is replaced by an aryl or heteroaryl ring is described. These new series of aryl[a]pyrrolo[3,4-c]carbazoles were evaluated as inhibitors of Cyclin D1-CDK4. A potent and selective D1-CDK4 inhibitor, 7a (D1-CDK4 IC(50)=45 nM), has been identified. The potency, selectivity profile against other kinases, and structure-activity relationship (SAR) trends of this class of compounds are discussed.
Sanchez-Martinez
Concha
C
DCR&T, Lilly Spain S.A., Avda de la Industria 30, 28108 Alcobendas, Madrid, Spain. sanchez-martinez_concepcion@lilly.com
Shih
Chuan
C
Faul
Margaret M
MM
Zhu
Guoxin
G
Paal
Michael
M
Somoza
Carmen
C
Li
Tiechao
T
Kumrich
Christine A
CA
Winneroski
Leonard L
LL
Xun
Zhou
Z
Brooks
Harold B
HB
Patel
Bharvin K R
BK
Schultz
Richard M
RM
DeHahn
Tammy B
TB
Spencer
Charles D
CD
Watkins
Scott A
SA
Considine
Eileen
E
Dempsey
Jack A
JA
Ogg
Catherine A
CA
Campbell
Robert M
RM
Anderson
Bryan A
BA
Wagner
Jill
J
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D011518:Proto-Oncogene Proteins; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002227:Carbazoles; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; C089657:arcyriaflavin A; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases