title: Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer.
abstract: Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2's small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (K(i) = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.
authors.affiliation: Cylene Pharmaceuticals, 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States. fpierre@cylenepharma.com
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.forename: Peter C
authors.initials: PC
authors.lastname: Chua
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Pauline
authors.initials: P
authors.lastname: Bourbon
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Jerome
authors.initials: J
authors.lastname: Michaux
authors.forename: Johnny
authors.initials: J
authors.lastname: Nagasawa
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schwaebe
authors.forename: Eric
authors.initials: E
authors.lastname: Stefan
authors.forename: Anne
authors.initials: A
authors.lastname: Vialettes
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Whitten
authors.forename: Ta Kung
authors.initials: TK
authors.lastname: Chen
authors.forename: Levan
authors.initials: L
authors.lastname: Darjania
authors.forename: Ryan
authors.initials: R
authors.lastname: Stansfield
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: Josh
authors.initials: J
authors.lastname: Bliesath
authors.forename: Denis
authors.initials: D
authors.lastname: Drygin
authors.forename: Caroline
authors.initials: C
authors.lastname: Ho
authors.forename: May
authors.initials: M
authors.lastname: Omori
authors.forename: Chris
authors.initials: C
authors.lastname: Proffitt
authors.forename: Nicole
authors.initials: N
authors.lastname: Streiner
authors.forename: Katy
authors.initials: K
authors.lastname: Trent
authors.forename: William G
authors.initials: WG
authors.lastname: Rice
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008958:Models, Molecular; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010619:Phenazines; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines; D010619:Phenazines; D000255:Adenosine Triphosphate; C555142:silmitasertib; D047390:Casein Kinase II