ML105 : CLK4 (Dual Specificity CDC-like kinase 4) Inhibitor
ML105
Target Name
Dual Specificity CDC-like kinase 4
Target Alias
CLK4
Target Class
Serine/ Threonine Protein Kinase
Mechanism of Action
Inhibitor of CLK4
Biological / Disease Relevance
Pre-mRNA splicing, Splicing modulators
In vitro activity
Clk4 assay (IC50)Target Information
The cdc2-like kinases (Clk) are made up of 4 isoforms (Clk1, Clk2, Clk3 and clk4). The Clk kinases are capable of both autophosphorylation and the phosphorylation of exogenous substrates. Importantly, the Clk family has been shown to be important constructs for the phosphorylation of serine and arginine rich (SR) proteins that are key components of the splicesome (Muraki 2004). Based upon these data (and other reports) the Clk kinases potentially play an important role in RNA splicing.
ML105 is a member of a series of inhibitors for Clk4 (CDC-like kinase 4). This compound can be used to study the implications of Clk4 in gene splicing events and other cellular events.
Properties
ML105
NCGC00012420
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 306.32 g/mol | |||
| Molecular Formula | C17H14N4O2 | |||
| cLogP | 2.4 | |||
| PSA | 69.2 | |||
| Storage | ||||
| Solubility | 10 mM in DMSO | |||
| CAS Number | ||||
SMILES:
C1(NCC2=CN=CC=C2)=NC(C3=CC4=C(OCO4)C=C3)=NC=C1
InChI:
InChI=1S/C17H14N4O2/c1-2-12(9-18-6-1)10-20-16-5-7-19-17(21-16)13-3-4-14-15(8-13)23-11-22-14/h1-9H,10-11H2,(H,19,20,21)
InChIKey:
QNQZGEQPXVSUOZ-UHFFFAOYSA-N
Activity
Summary activity statement /
ML105 (SID 4239891; CID 3234998, NCGC 00012420) is a member of a series of highly specific inhibitors of the Clk family of kinases (CDC like kinases) with registered activity versus Clk4 at 30 nM. Profiles of this agent suggest that this agent has low nM activity versus the other 3 members of this family (Clk1, Clk2 and Clk3) and Drk1A. The only other reported Clk4 inhibitor is TG003 (reported IC50 of 15 nM; IC50 value of 44 nM in our study) (Muraki 2004) was found to be far more promiscuous versus the same panel (Figure 1).
Figure 1. Kinase profiles were performed by Ambit Biosciences (San Diego, CA, USA) utilizing KINOMEscan™. Activity was recorded via a competition binding assay of selected kinases that are fused to a proprietary tag. Measurements of the amount of kinase bound to an immobilized, active-site directed ligand in the presence and absence of the test compound provide a % of DMSO control for binding of ligand. Activities between 0 and 10 were selected for Kd determinations. Two Clk4 inhibitors were test at 10 uM: probe analog ML106 (A), TG003 (B). Dendrogram representations were generated by an inhouse visualization tool designated PhyloChem. Dendrogram clustering and apexes are based on the human phylogenetic kinase data.
References
- qHTS for Inhibitors of CDC-like Kinase 4: Summary
- Muraki, M.; Ohkawara, B.; Hosoya, T.; Onogi, H.; Koizumi, J.; Koizumi, T.; Sumi, K.; Yomoda, J.; Murray, M. V.; Kimura, H.; Furuichi, K.; Shibuya, H.; Krainer, A. R.; Suzuki, M.; Hagiwara, M. Manipulation of alternative splicing by a newly developed inhibitor of Clks. J Biol Chem 2004, 279, 24246-54
- Auld D, Shen M, Thomas C. A high-throughput screen for pre-mRNA splicing modulators. 2009 May 18 [Updated 2010 Sep 2]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010
- Rosenthal AS, Tanega C, Shen M, et al. Potent and selective small molecule inhibitors of specific isoforms of Cdc2-like kinases (Clk) and dual specificity tyrosine-phosphorylation-regulated kinases (Dyrk). Bioorg Med Chem Lett. 2011;21(10):3152-3158. doi:10.1016/j.bmcl.2011.02.114