Development of a protein-protein interaction inhibitor of SRPK1 that inhibits angiogenesis
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AbstractSerine-arginine rich proteins (SR proteins) are a family of non-snRNP splicing factors that are essential for both constitutive and alternative splicing. They are extensively phosphorylated at multiple serine residues at their C-terminal arginine-serine (RS) domain, which are crucial to the regulation of spliceosome assembly, splice site selection, mRNA export, and translation. SR protein kinases (SRPKs) have been established as the major kinase family that phosphorylates SR proteins and regulate pre-mRNA splicing. Given their key roles in splicing regulation, abnormal expression or misregulation of SRPKs have been implicated in many diseases including multiple forms of cancer, Alzheimer’s disease, and the infection of viruses like HIV-1, HBV and HCV, suggesting that SRPKs represent new candidates for targeted therapeutics. Indeed, a number of studies have shown that knockdown or inhibition of SRPK1, the prototypic member of the family, has anti-tumoral effects. Several inhibitors of SRPK1, which all belong to the ATP-competitive class, have been reported thus far. However, ATP-competitive inhibitors must contend with the intracellular levels of ATP and more importantly may suffer from drug resistance caused by the development of resistance mutations at the ATP-bind clefts of the target kinases. Such mutations, which hinder drug binding but preserve the kinase catalytic activity, have been observed in many kinases targeted by clinically-approved ATP-competitive small molecule inhibitors.
Therefore, new strategy is required to develop novel SRPK1 inhibitor(s) that can overcome these caveats. We have recently developed a peptide inhibitor that targets a critical substrate docking groove in SRPK1. This inhibitor competes with the binding and phosphorylation of the prototypic SR protein SRSF1, which subsequently alters VEGF splicing and inhibits angiogenesis. Our work demonstrates that peptide inhibitor targeting the protein-protein interaction site between SRPK1 and its substrate is a feasible strategy. In addition, this inhibitor could be used together with ATP-competitive inhibitors to achieve synergistic inhibitory effect.
Acceptance Date14/09/2019
All Author(s) ListJacky Chi Ki Ngo
Name of Conference10th Inhibitors of Protein Kinases 2019
Start Date of Conference14/09/2019
End Date of Conference19/09/2019
Place of ConferenceWarsaw
Country/Region of ConferencePoland
LanguagesEnglish-United States

Last updated on 2020-23-11 at 18:57