A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore
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- 作者：Yihui Shi ; Jaehyeon Park ; Chandraiah Lagisetti ; Wei Zhou ; Lidia C. Sambucetti ; Thomas R. Webb ; thomas.webb@sri.com
- 关键词：CLK ; cdc2-like kinase ; MDM2 ; mouse double minute 2 homolog ; Luc ; luciferase ; TEA ; triethylamine ; DIPEA ; diisopropylethylamine ; EtOAc ; ethyl acetate
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2017
- 出版时间：1 February 2017
- 年：2017
- 卷：27
- 期：3
- 页码：406-412
- 全文大小：1987 K
- 卷排序：27
文摘
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.