title: Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties.
abstract: The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC₅₀ ≤ 50 nM versus CK1δ. The two lead compounds have ≤100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.
authors.affiliation: Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bibian
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Rahaim
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Stephan
authors.initials: S
authors.lastname: Schürer
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Shima
authors.initials: S
authors.lastname: Nakanishi
authors.forename: Konstantin
authors.initials: K
authors.lastname: Licht
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rosenberg
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D011687:Purines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; C585784:SR-2890; C585785:SR-3029; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; C030985:purine