title: Pre-clinical characterization of CX-4945, a potent and selective small molecule inhibitor of CK2 for the treatment of cancer.
abstract: In this article we describe the preclinical characterization of 5-(3-chlorophenylamino) benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM). Iterative synthesis and screening of analogs, guided by molecular modeling, led to the discovery of orally available CX-4945. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry. Inhibition of the newly validated CK2 target by CX-4945 represents a fresh therapeutic strategy for cancer.
authors.affiliation: Cylene Pharmaceuticals, San Diego, CA 92121, USA. 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: Joshua
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: William G
authors.initials: WG
authors.lastname: Rice
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010619:Phenazines; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C555142:silmitasertib; D047390:Casein Kinase II; D053148:Caspase 3; D053179:Caspase 7