Biologically Driven Synthesis of Pyrazolo[3,4-d]pyrimidines As Protein Kinase Inhibitors: An Old Scaffold As a New Tool for Medicinal Chemistry and Chemical Biology Studies

2014 ◽  
Vol 114 (14) ◽  
pp. 7189-7238 ◽  
Author(s):  
Silvia Schenone ◽  
Marco Radi ◽  
Francesca Musumeci ◽  
Chiara Brullo ◽  
Maurizio Botta
Keyword(s):  
Protein Kinase ◽  
Chemical Biology ◽  
Medicinal Chemistry ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors

scholarly journals Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

RSC Advances ◽  
2021 ◽  
Vol 11 (41) ◽  
pp. 25228-25257
Author(s):  
Nitin Tandon ◽  
Vijay Luxami ◽  
Divya Kant ◽  
Runjhun Tandon ◽  
Kamaldeep Paul
Keyword(s):  
Protein Kinase ◽  
Medicinal Chemistry ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Future Prospects

The indazole core is an interesting pharmacophore due to its applications in medicinal chemistry.

scholarly journals New tools for evaluating protein tyrosine sulphation: Tyrosyl Protein Sulphotransferases (TPSTs) are novel targets for RAF protein kinase inhibitors

2018 ◽  
Author(s):  
Dominic P Byrne ◽  
Yong Li ◽  
Pawin Ngamlert ◽  
Krithika Ramakrishnan ◽  
Claire E Eyers ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Small Molecule ◽  
Protein Interactions ◽  
Chemical Biology ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Post Translational Modification ◽  
Protein Tyrosine

ABSTRACTProtein tyrosine sulphation is a post-translational modification (PTM) best known for regulating extracellular protein-protein interactions. Tyrosine sulphation is catalysed by two Golgi-resident enzymes termed Tyrosyl Protein Sulpho Transferases (TPSTs) 1 and 2, which transfer sulphate from the co-factor PAPS (3’-phosphoadenosine 5’-phosphosulphate) to a context-dependent tyrosine in a protein substrate. A lack of quantitative tyrosine sulphation assays has hampered the development of chemical biology approaches for the identification of small molecule inhibitors of tyrosine sulphation. In this paper, we describe the development of a non-radioactive mobility-based enzymatic assay for TPST1 and TPST2, through which the tyrosine sulphation of synthetic fluorescent peptides can be rapidly quantified. We exploit ligand binding and inhibitor screens to uncover a susceptibility of TPST1 and 2 to different classes of small molecules, including the anti-angiogenic compound suramin and the kinase inhibitor rottlerin. By screening the Published Kinase Inhibitor Set (PKIS), we identified oxindole-based inhibitors of the Ser/Thr kinase RAF as low micromolar inhibitors of TPST1/2. Interestingly, unrelated RAF inhibitors, exemplified by the dual BRAF/VEGFR2 inhibitor RAF265, were also TPST inhibitors in vitro. We propose that target-validated protein kinase inhibitors could be repurposed, or redesigned, as more-specific TPST inhibitors to help evaluate the sulphotyrosyl proteome. Finally, we speculate that mechanistic inhibition of cellular tyrosine sulphation might be relevant to some of the phenotypes observed in cells exposed to anionic TPST ligands and RAF protein kinase inhibitors.SUMMARY STATEMENTWe develop new assays to quantify tyrosine sulphation by the human tyrosine sulphotransferases TPST1 and 2. TPST1 and 2 catalytic activities are inhibited by protein kinase inhibitors, suggesting new starting points to synthesise (or repurpose) small molecule compounds to evaluate biological TPST using chemical biology.

scholarly journals Thiazolidine-diones. Biochemical and biological activity of a novel class of tyrosine protein kinase inhibitors.

1990 ◽  
Vol 265 (36) ◽  
pp. 22255-22261
Author(s):  
J F Geissler ◽  
P Traxler ◽  
U Regenass ◽  
B J Murray ◽  
J L Roesel ◽  
...  
Keyword(s):  
Biological Activity ◽  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Tyrosine Protein Kinase
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