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Kinase probes The highly selective ERK1/2 inhibitor SCH772984 revealed a new binding mode targeting an allosteric pocket created by an outward movement of helix aC and distortion of the P-loop (Nat Chem Biol. 2014 Oct;10(10):853-60).

 

Kinase Chemical Probes

The human kinome constitutes a large protein superfamily of more than 500 members. Protein kinases are deregulated in many diseases and have been therefore extensively targeted for the development of new medicines. These efforts led to the approval of more than 30 drugs during the past 15 years. However, despite the large investment of academia and pharmaceutical industry in kinase drug discovery, only a small fraction of protein kinases have been studied in detail and currently the role of most kinases in cellular signalling and in the development of diseases remains unknown. We initiated therefore a kinase chemical probe program which is a joined effort of scientists at SGC sites in Frankfurt, Oxford, UNC, Karolinska Institute and Unicamp at Campinas as well as a large number of academic and industrial collaborators.
Goal of the program is to provide and develop the best possible chemical probes for kinase targets. Due to the large size of this protein family a comprehensive chemogenomics set covering all kinases is currently assembled at the UNC which will serve as a tool as long as many kinase family members cannot be studied by highly selective probe compounds.
Developing highly specific inhibitors for protein kinases is due to the conservation if the ATP binding site a tremendous challenge. The Frankfurt SGC laboratory is therefore particularly interested in developing allosteric kinase inhibitors that bind to target specific pockets adjacent or distantly located to the ATP site, covalent inhibitors that target unique cysteine residues as well as macrocyclic inhibitors with optimal shape compatibility to the ATP binding pocket. Allosteric inhibitors may also allow modulating scaffolding functions of kinases, an important role but poorly understood role of protein kinases that has led to unexpected signalling events of some drugs and drug candidates. Allosteric inhibitors may also allow us targeting of pseudokinases, a considerable subset of protein kinases with no or little catalytic activity that has been associated with the development of a large diversity of diseases.

BAY-474 BAY-826 FM-381 BAY-826 MRL-SYKi PF-04554878 PF-04554878 DDR-TRK-1 DDR-TRK-1 DDR-TRK-1 BAY-826 BAY-826 DDR-TRK-1 DDR-TRK-1 T3-CLK T3-CLK T3-CLK T3-CLK T3-CLK T3-CLK T3-CLK MU1210 MU1210 MU1210 T3-CLK BAY-885 ERKi ERKi SGC-GAK-1 BAY-3827 BAY-3827 NVS-PAK1-1 MLi-2 TH-257 TH-257 TP-008 TP-008