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Chop-and-change at the protein plant –

Novel inhibitor modulates alternative splicing

Munich, 03/23/2011

Ribonucleic acids (RNAs) are highly versatile, and one sort is essential for protein synthesis. The RNAs known as messenger RNAs (mRNAs), which are copies (“transcripts”) of genomic DNA, serve as blueprints for the production of proteins in all cells. The primary RNA-transcript of a gene is a precursor form (pre-mRNA), which needs to be processed into functional mRNA. During processing, defined segments of the precursor are removed and the remaining fragments are spliced together. Thanks to the phenomenon of alternative splicing, differently processed forms of the same mRNA precursor may code for different proteins. Splicing requires the coordinated action of many proteins, and enzymes called Cdc2-like kinases (CLKs), which activate other proteins, are especially important. A research team led by medicinal chemist Professor Franz Bracher at Ludwig-Maximilians-Universität (LMU) in Munich in cooperation with Professor Stefan Knapp at Oxford University, has now developed a highly potent and extremely selective inhibitor named KH-CB19, which blocks the action of these enzymes. Pharmacologic studies at Charité Hospital in Berlin have shown that the compound exerts an effect at very low doses. “This makes the new inhibitor an excellent chemical tool for probing the biological significance of alternative splicing,” says Bracher. “It could also facilitate the development of new agents for the treatment of influenza.” (Chemistry & Biology, January 2011).

One gene, one protein. That used to be a dogma, but it has long been discarded. Thanks to alternative splicing, it is possible for a single gene to code for several proteins with different functions, and about 90% of human genes fall into this category. Indeed, proteins that have opposing functions may be derived from one gene. For example, two different products of one gene stimulate or inhibit the formation of new blood vessels. Similar variants also play a role in controlling blood coagulation and blood glucose levels. Not surprisingly, errors in alternative splicing can lead to disease states including cancer and other conditions.

Regulation of the splicing process depends on the precisely orchestrated interplay of a large number of proteins and accessory factors. Among these, the so-called SR proteins, which are rich in the amino acids serine and arginine, control the selection of transcripts for processing. By adding phosphate groups to some of the serine residues, CLKs and other kinases regulate the cellular localization and activity of the SR proteins. Bracher’s research group has now developed the compound KH-CB19, a highly selective and very potent inhibitor that specifically targets CLK isoforms 1 and 4.

Tests carried out in cooperation with Knapp’s team in Oxford have now revealed that the exceptionally high selectivity of the novel compound is due to its unique chemical structure. In experiments on cells exposed to inflammatory stimuli, performed at Professor Ursula Rauch‘s laboratory at the Center for Cardiovascular Medicine at the Charité Hospital in Berlin, KH-CB19 was found to alter the relative levels of two splice isoforms of human tissue factor which are involved in the regulation of blood clotting.

“These results suggest that with KH-CB19 we have in hand a first-rate tool for further research on alternative splicing,” says Bracher. “Its remarkable selectivity and potency also make the molecule very interesting from a therapeutic point of view. Recent results have shown that CLK inhibitors like KH-CB19 could open up new options for the treatment of influenza infections, for instance, and further studies in this direction are underway. The new inhibitor might even turn out to provide a structural basis for the development of a whole new class of therapeutic drugs.” (göd/PH)


"Specific CLK Inhibitors from a Novel Chemotype for Regulation of Alternative Splicing"
Oleg Fedorov, Kilian Huber, Andreas Eisenreich, Panagis Filippakopoulos, Oliver King, Alex N. Bullock, Damian Szklarczyk, Lars J. Jensen, Doriano Fabbro, Jörg Trappe, Ursula Rauch, Franz Bracher, Stefan Knapp.
Chemistry & Biology 2011, vol. 18, pp. 67-76.
PubMed ID: 21276940

Prof. Dr. Franz Bracher
Department of Pharmacy – Center of Drug Research
Phone: +49 (0) 89/2180 – 77301

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