title: Aryl[a]pyrrolo[3,4-c]carbazoles as selective cyclin D1-CDK4 inhibitors.
abstract: 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.
authors.affiliation: DCR&T, Lilly Spain S.A., Avda de la Industria 30, 28108 Alcobendas, Madrid, Spain. sanchez-martinez_concepcion@lilly.com
authors.forename: Concha
authors.initials: C
authors.lastname: Sanchez-Martinez
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Faul
authors.forename: Guoxin
authors.initials: G
authors.lastname: Zhu
authors.forename: Michael
authors.initials: M
authors.lastname: Paal
authors.forename: Carmen
authors.initials: C
authors.lastname: Somoza
authors.forename: Tiechao
authors.initials: T
authors.lastname: Li
authors.forename: Christine A
authors.initials: CA
authors.lastname: Kumrich
authors.forename: Leonard L
authors.initials: LL
authors.lastname: Winneroski
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xun
authors.forename: Harold B
authors.initials: HB
authors.lastname: Brooks
authors.forename: Bharvin K R
authors.initials: BK
authors.lastname: Patel
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schultz
authors.forename: Tammy B
authors.initials: TB
authors.lastname: DeHahn
authors.forename: Charles D
authors.initials: CD
authors.lastname: Spencer
authors.forename: Scott A
authors.initials: SA
authors.lastname: Watkins
authors.forename: Eileen
authors.initials: E
authors.lastname: Considine
authors.forename: Jack A
authors.initials: JA
authors.lastname: Dempsey
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Ogg
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Anderson
authors.forename: Jill
authors.initials: J
authors.lastname: Wagner
mesh_terms: 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*
chemical_list: 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