Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands

Murár, Miroslav; Dobiáš, Juraj; Šramel, Peter; Addová, Gabriela; Hanquet, Gilles; Boháč, Andrej

doi:10.1016/j.ejmech.2016.11.003

Cited by 21 publications

(9 citation statements)

References 26 publications

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“…6c ). There is interest in the potential of targeting CLK1 in the context of the influenza [ 35 ] and HIV-1 viruses [ 36 ] and in cancer cells [ 37 , 38 ]. The fact that CLK kinases appear to help cancer cells adapt to hypoxia suggests that they could be useful therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells

et al. 2018

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BackgroundMounting evidence suggests that one of the ways that cells adapt to hypoxia is through alternative splicing. The aim of this study was firstly to examine the effect of hypoxia on the alternative splicing of cancer associated genes using the prostate cancer cell line PC3 as a model. Secondly, the effect of hypoxia on the expression of several regulators of splicing was examined.MethodsPC3 cells were grown in 1% oxygen in a hypoxic chamber for 48 h, RNA extracted and sent for high throughput PCR analysis at the RNomics platform at the University of Sherbrooke, Canada. Genes whose exon inclusion rate PSI (ψ) changed significantly were identified, and their altered exon inclusion rates verified by RT-PCR in three cell lines. The expression of splice factors and splice factor kinases in response to hypoxia was examined by qPCR and western blotting. The splice factor kinase CLK1 was inhibited with the benzothiazole TG003.ResultsIn PC3 cells the exon inclusion rate PSI (ψ) was seen to change by > 25% in 12 cancer-associated genes; MBP, APAF1, PUF60, SYNE2, CDC42BPA, FGFR10P, BTN2A2, UTRN, RAP1GDS1, PTPN13, TTC23 and CASP9 (caspase 9). The expression of the splice factors SRSF1, SRSF2, SRSF3, SAM68, HuR, hnRNPA1, and of the splice factor kinases SRPK1 and CLK1 increased significantly in hypoxia. We also observed that the splice factor kinase CLK3, but not CLK2 and CLK4, was also induced in hypoxic DU145 prostate, HT29 colon and MCF7 breast cancer cell lines. Lastly, we show that the inhibition of CLK1 in PC3 cells with the benzothiazole TG003 increased expression of the anti-apoptotic isoform caspase 9b.ConclusionsSignificant changes in alternative splicing of cancer associated genes occur in prostate cancer cells in hypoxic conditions. The expression of several splice factors and splice factor kinases increases during hypoxia, in particular the Cdc-like splice factor kinases CLK1 and CLK3. We suggest that in hypoxia the elevated expression of these regulators of splicing helps cells adapt through alternative splicing of key cancer-associated genes. We suggest that the CLK splice factor kinases could be targeted in cancers in which hypoxia contributes to resistance to therapy.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4227-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells

et al. 2018

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“…The CLK2- 20 cocrystal complex (PDB id: 3NR9) indicated that the nitrogen of quinoline interacted with Leu246 and 2-aminothiazol-4-one formed hydrogen bonds with Lys193 and Asp327. The thiophene and quinoline formed π–π interactions with Phe174 and Phe243, respectively. , Quinoline derivative 20 has promoted the subsequent development of CLK2 inhibitors as a tool compound.…”

Section: Disclosed Clk2 Inhibitorsmentioning

confidence: 99%

Development of Cdc2-like Kinase 2 Inhibitors: Achievements and Future Directions

Qin

Feng

et al. 2021

J. Med. Chem.

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Cdc2-like kinases (CLKs; CLK1–4) are associated with various neurodegenerative disorders, metabolic regulation, and viral infection and have been recognized as potential drug targets. Human CLK2 has received increasing attention as a regulator that phosphorylates serine- and arginine-rich (SR) proteins and subsequently modulates the alternative splicing of precursor mRNA (pre-mRNA), which is an attractive target for degenerative disease and cancer. Numerous CLK2 inhibitors have been identified, with several molecules currently in clinical development. The first CLK2 inhibitor Lorecivivint (compound 1) has recently entered phase 3 clinical trials. However, highly selective CLK2 inhibitors are rarely reported. This Perspective summarizes the biological roles and therapeutic potential of CLK2 along with progress on the development of CLK2 inhibitors and discusses the achievements and future prospects of CLK2 inhibitors for therapeutic applications.

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“…Notably, SM08502, a CLK1 inhibitor, recently entered clinical trials for the treatment of advanced solid tumors ( Tam et al, 2020 ). Additionally, pharmacological inhibition of CLK1 has been investigated pre-clinically for the treatment of Duchenne muscular dystrophy ( Sako et al, 2017 ) and Alzheimer’s disease ( Jain et al, 2014 ; Hedou et al, 2016 ; Murar et al, 2017 ). Beyond these diseases, it was reported that lower temperature causes CLK1 activation in vitro in cultured HEK293 cells ( Haltenhof et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of a Novel CLK1-THRAP3-PPARγ Axis Improves Insulin Sensitivity

Wang

Gao

et al. 2021

Front. Physiol.

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Increasing energy expenditure by promoting “browning” in adipose tissues is a promising strategy to prevent obesity and associated diabetes. To uncover potential targets of cold exposure, which induces energy expenditure, we performed phosphoproteomics profiling in brown adipose tissue of mice housed in mild cold environment at 16°C. We identified CDC2-like kinase 1 (CLK1) as one of the kinases that were significantly downregulated by mild cold exposure. In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22°C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays. We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPARγ), resulting in impaired adipose tissue browning and insulin sensitivity. These data suggest that CLK1 plays a critical role in controlling energy expenditure through the CLK1-THRAP3-PPARγ axis.

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Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands

Cited by 21 publications

References 26 publications

Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells

Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells

Development of Cdc2-like Kinase 2 Inhibitors: Achievements and Future Directions

Inhibition of a Novel CLK1-THRAP3-PPARγ Axis Improves Insulin Sensitivity

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