Roscovitine-Derived, Dual-Specificity Inhibitors of Cyclin-Dependent Kinases and Casein Kinases 1

Abstract

Cyclin-dependent kinases (CDKs) and casein kinases 1 (CK1) are involved in the two key molecular features of Alzheimer's disease, production of amyloid-beta peptides (extracellular plaques) and hyper-phosphorylation of Tau (intracellular neurofibrillary tangles). A series of 2,6,9-trisubstituted purines, structurally related to the CDK inhibitor roscovitine, have been synthesized. They mainly differ by the substituent on the C-6 position. These compounds were screened for kinase inhibitory activities and antiproliferative effects. Several biaryl derivatives displayed potent inhibition of both CDKs and CK1. In particular, derivative 13a was a potent inhibitor of CDK1/cyclin B (IC 50: 220 nM), CDK5/p25 (IC 50: 80 nM), and CK1 (IC 50: 14 nM). Modeling of these molecules into the ATP-binding pocket of CK1delta provided a rationale for the increased selectivity toward this kinase. 13a was able to prevent the CK1-dependent production of amyloid-beta in a cell model. CDK/CK1 dual-specificity inhibitors may have important applications in Alzheimer's disease and cancers.

From Drug Screening to Target Deconvolution: a Target-Based Drug Discovery Pipeline Using Leishmania Casein Kinase 1 Isoform 2 To Identify Compounds with Antileishmanial Activity

“…We used CK-S as the substrate for both kinases and 15 M [␥- 33 P]ATP for the assay (21,23). We screened 4,030 compounds at 10 M from a kinase-biased library that has been previously tested on mammalian kinases, such as cyclin-dependent kinases (29). For each compound, the percent inhibition of LmCK1.2 versus that of SsCK1 is presented in Fig.…”

“…We screened 5,018 compounds from the Roscoff library including 588 purine derivatives (29) and 400 indirubin derivatives (30,31,32).…”

Inhibition of NF-κB–Mediated Signaling by the Cyclin-Dependent Kinase Inhibitor CR8 Overcomes Prosurvival Stimuli to Induce Apoptosis in Chronic Lymphocytic Leukemia Cells

“…Synthesis of (R)-DH22 [2], (R)-ML20 [3], (R)-ML76 [4], (R)-CR3 [5], (R)-ML78 [6], (R)-CR4 [7], (R)-CR1 [10], (R)-CR2 [11], (R)-CR11 [12], and (R)-Ness2 [13] is provided in ref. (22).…”

“…Dose-response curves enabled IC 50 calculation. CDK2/cyclin A and CDK9/cyclin T (human, recombinant, expressed in insect cells) were prepared as described previously (19,22). Kinase activity was assayed with either 1 mg/mL histone H1 type III-S (Sigma-Aldrich; CDK2) or 8.07 mg/assay CDK7/9 tide (YSPTSPSYSPTSP-SYSPTSPSKKKK; CDK9; Millegen), with 15 mmol/L [g- 33 P] ATP (3,000 Ci/mmol; 10 mCi/mL) in a 30 mL final volume.…”

Forebrain overexpression of CK1δ leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD

“…The CK1 Ser/Thr kinase family plays a crucial role in numerous biological functions ranging from cell cycle regulation (1)(2)(3)(4)(5) to more complex behavioral traits (6)(7)(8). In the central nervous system, CK1δ is involved in a variety of physiological (e.g., cell signaling, circadian rhythm, cellular trafficking) and pathological (e.g., amyloid-β formation and tauopathies) processes (9)(10)(11)(12)(13)(14). In the basal ganglia, CK1 regulates the state of phosphorylation of DARPP-32 (dopamine-and cAMP-regulated phospho-protein Mw of 32 kDa), a key striatal protein, which integrates synaptic input signals from various origins including the dopaminergic and glutamatergic systems (15)(16)(17).…”