title: Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization.
abstract: Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC(50) value of 78 nM.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #1 Keyuan Road 4, Sichuan 610041, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Li
authors.forename: Heng-Xiu
authors.initials: HX
authors.lastname: Yan
authors.forename: Qi-Zheng
authors.initials: QZ
authors.lastname: Sun
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Ze-Rong
authors.initials: ZR
authors.lastname: Wang
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Jun
authors.initials: J
authors.lastname: Zou
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D047389:Casein Kinase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003959:Diamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D003959:Diamines; C580707:N6-phenyl-1H-pyrazolo(3,4-d)pyrimidine-3,6-diamine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D047389:Casein Kinase I