A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore |
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Authors: | Yihui Shi Jaehyeon Park Chandraiah Lagisetti Wei Zhou Lidia C Sambucetti Thomas R Webb |
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Institution: | Division of Biosciences, SRI International, 333 Ravenswood Ave., Menlo Park, CA 94025, USA |
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Abstract: | The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors. We found that these compounds, and their analogs, show significant cdc2-like kinase (CLK) inhibition and clear structure-activity relationships (SAR) at CLKs. We prepared a set of analogs and were able to ‘dial out’ the CDK activity and simultaneously developed CLK inhibitors with low nanomolar activity. Thus, we have demonstrated the utility of our exon-skipping assay and identified new molecules that exhibit potency and selectivity for CLK, as well as some structurally related dual CLK/CDK inhibitors. |
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Keywords: | CLK cdc2-like kinase MDM2 mouse double minute 2 homolog Luc luciferase TEA triethylamine DIPEA diisopropylethylamine EtOAc ethyl acetate Cdc-like kinase (CLK) inhibitors Modulators of pre-mRNA splicing High throughput screening Anti-tumor agents |
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