190654-04-7Relevant academic research and scientific papers
A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore
Shi, Yihui,Park, Jaehyeon,Lagisetti, Chandraiah,Zhou, Wei,Sambucetti, Lidia C.,Webb, Thomas R.
, p. 406 - 412 (2017)
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.
DUAL CLK/CDK1 INHIBITORS FOR CANCER TREATMENT
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Paragraph 00324; 00325, (2018/06/16)
This disclosure generally relates to dual CLK2/CDK1 inhibitors or more potent and specific CLK inhibitors to target CLK2 and CDKl kinases in the treatment of germ-line mutations of the spliceosome leading to the development of cancers and other human dise
