title: Synthesis and SAR of inhibitors of protein kinase CK2: novel tricyclic quinoline analogs.
abstract: Protein kinase CK2 is a potential drug target for many diseases including cancer and inflammation disorders. The crystal structure of clinical candidate CX-4945 1 with CK2 revealed an indirect interaction with the protein through hydrogen bonding between the NH of the 3-chlorophenyl amine and a water molecule. Herein, we investigate the relevance of this hydrogen bond by preparing several novel tricyclic derivatives lacking a NH moiety at the same position. This SAR study allowed the discovery of highly potent CK2 inhibitors.
authors.affiliation: Cylene Pharmaceuticals Inc., 5820 Nancy Ridge Drive, Suite 200, San Diego, CA 92121, USA. mhaddach@cylenepharma.com
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.forename: Collin F
authors.initials: CF
authors.lastname: Regan
authors.forename: Cosmin
authors.initials: C
authors.lastname: Borsan
authors.forename: Jerome
authors.initials: J
authors.lastname: Michaux
authors.forename: Eric
authors.initials: E
authors.lastname: Stefan
authors.forename: Pauline
authors.initials: P
authors.lastname: Kerdoncuff
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.forename: Peter C
authors.initials: PC
authors.lastname: Chua
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Diwata
authors.initials: D
authors.lastname: Macalino
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011804:Quinolines; D047390:Casein Kinase II