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

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 IC50 value of 78 nM.

Pharmacophore-based virtual screening together with subsequent hit-to-lead optimization led to the discovery of a new lead compound that potently inhibits CK1 with an IC50 value of 78 nM.Figure optionsDownload as PowerPoint slideHighlights
► We described a newly proposed pharmacophore modeling protocol.
► We developed an optimal pharmacophore model of CK1, termed Hypo2.
►  Hypo2 was used to retrieve potential CK1 inhibitors from several chemical databases.
► Further structural optimization was carried out on one of the best hit compounds.
► We discovered a new lead compound that inhibits CK1 with an IC50 value of 78 nM.