Alternative splicing is an essential process in eukaryotes often following the transcription of DNA into pre-mRNA. The removal or retention of exons from a single pre-mRNA during splicing gives rise to an array of different mRNAs and subsequently translated proteins. Among other regulatory mechanisms involved in this process, phosphorylation of splicing factors by kinases of the CLK family (CDC2-like kinases) plays an important role. [1] Hence, any dysregulation of these kinases may alter or abolish the original function of an affected protein thus contributing to the development of diseases such as Alzheimer's disease or the metastasis of ovarian cancer. [2, 3] The relevance of CLKs in the onset of the abovementioned diseases and the lack of potent and selective inhibitors shows an unmet need for novel small molecules as tools for biological experiments or as lead compounds in the drug discovery process. We here present the synthesis and biological evaluation of 6,7-dihydropyrrolo[3,4-g]indol-8-ones which exhibit IC50-values for CLKs in the nanomolar range while being inactive on all members of a panel of related serine threonine kinases (e.g. DYRKs).References:1. Hagiwara, M., Alternative splicing: a new drug target of the post-genome era. Biochim. Biophys. Acta, 2005 , 1754, 324-331.2. Liu, Y., Conaway, L., Rutherford Bethard, J., Al-Ayoubi, A.M., Thompson Bradley, A., Zheng, H., Weed, S.A., Eblen, S.T., Phosphorylation of the alternative mRNA splicing factor 45 (SPF45) by CLK1 regulates its splice site utilization, cell migration and invasion. Nucleic Acids Res., 2013 , 41, 4949-4962.3. Glatz, D.C., Rujescu, D., Tang, Y., Berendt, F.J., Hartmann, A.M., Faltraco, F., Rosenberg, C., Hulette, C., Jellinger, K., Hampel, H., Riederer, P., Moller, H.J., Andreadis, A., Henkel, K., Stamm, S., The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2-BETA1 changes in sporadic Alzheimer's disease. J. Neurochem., 2006 , 96, 635-644.

6,7-Dihydropyrrolo[3,4-<i>g</i>]indol-8-ones as selective inhibitors of CDC2-like kinases (CLKs)

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

6,7-Dihydropyrrolo[3,4-g]indol-8-ones as selective inhibitors of CDC2-like kinases (CLKs)