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.

Figure 1

Representative CK1δ/ε inhibitors.

Figure 2

CK1δ/ε inhibition data for SR-1277 and SR-653234.

Figure 3

Strategy for synthesis of purine-scaffold CK1δ/ε inhibitors, illustrated by the synthesis of SR-653234. Conditions: (a) ArB(OH)₂, CuOAc₂, MS 4 Å, NEt₃, CH₂Cl₂, 24 h, 23 °C, 27 %; (b) 2-(aminomethyl)benzimidazole, (i-Pr)₂NEt, i-PrOH, 30 min, 90 °C, microwave; (c) morpholine, 130 °C, 30 min, microwave, 70%.

Figure 4

General method for synthesis of substituted 2-(aminomethyl)benzimidazoles. Conditions: (a) EDC·HCl, HOBt·H₂O, Boc-GlyOH, CH₂Cl₂, 23°C, 2 h; (b) AcOH (neat), 80 °C, 2 h; (c) HCl (12 N), dioxane, (1/1), overnight, 23 °C.

Figure 5

Poses of SR-1277 (left) and SR-1292 (right) docked into the CK1δ active site.

Figure 6

Dendrogram presentation of results of DiscoverRX^® KINOMEscan^® kinase binding selectivity analysis of PF-670462, SR-1277, SR-2890 and SR-3029. Data are presented for all kinases that have <10% control activity at 10 μM (% control is the percentage of kinase remaining bound to the bead-bound active-site ligand in the presence of the inhibitor).