Structure–Activity Relationship in the Leucettine Family of Kinase Inhibitors

Abstract

The protein kinase DYRK1A is involved in Alzheimer’s disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure–activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.

An overview of cdc2‐like kinase 1 (Clk1) inhibitors and their therapeutic indications

“…Despite being able to protect hippocampal HT22 cells from glutamate‐induced cell death, this neuroprotective effect was not confirmed to be related to Clk1 inhibition. Furthermore, additional experiments verified the ability of Leucettine L 41 to reduce neurodegeneration in brain slices transfected with amyloid precursor protein (APP), an effect that was proven to be related to Dyrk1A inhibition 90,120 …”

“…Later, Tahtouh et al provided advanced exploration of the SAR of the Leucettine derivatives, in an attempt to improve the potency and selectivity of L 41 ( 11 ) 118,120 . Analysis of the kinase data presented for the synthetic Leucettine derivatives in both studies 118,120 demonstrated that; (i) the 1,3 benzodioxole moiety at position 5, as well as N1, N3 and the carbonyl of the 2‐aminoimidazolin‐4‐one are crucial for Clk1/Dyrk1a inhibitory activity 118,120 ; (ii) adding a methyl substituent or reduction of the linker between benzodioxole and the 2‐aminoimidazolin‐4‐one was detrimental for activity 120 …”

“…Compounds ( 12 ) and ( 13 ) were the most potent Clk1/Dyrk1A inhibitors. Table 2 summarizes the kinase data for compounds ( 12) and ( 13) 120 …”

“…Later on, Tahtouh et al 90 (11). 118,120 Analysis of the kinase data presented for the synthetic Leucettine derivatives in both studies 118,120 demonstrated that; (i) the 1,3 benzodioxole moiety at position 5, as well as N1, N3 and the carbonyl of the 2-aminoimidazolin-4-one are crucial for Clk1/Dyrk1a inhibitory activity 118,120 ; (ii) adding a methyl substituent or reduction of the linker between benzodioxole and the 2-aminoimidazolin-4-one was detrimental for activity. 120 The recent study made by Tahtouh et al focused on the substitution at the exocyclic amine present in the 2-aminoimidazolin-4-one core.…”

“…Table 2 summarizes the kinase data for compounds (12) and ( 13). 120 The synthetic Leucettine L 41 (11) was studied in various cell experiments where it significantly reduced the phosphorylation of SRSF4 and SRSF6 (two downstream targets of Clk1) in tumor necrosis factor-α (TNF-α) stimulated or unstimulated human microvascular endothelial cells (HMEC-1) in a concentration-dependent manner. 118 Moreover, Leucettine L 41 (11) succeeded in modulating the alternative splicing of synthetic Clk1 minigene transfected into Hela cells.…”