A small molecule bidentate binding dual inhibitor probe of the LRRK2 and JNK kinases

The major challenge in developing kinase inhibitors is to gain high selectivity and affinity in order to diminish PI-103 off-target side effects. As we know, the majority of kinase inhibitors (type-I inhibitors) developed so far are ATP-competitive, and their selectivity can be low due to binding in the highly conserved ATP-binding pocket. Additionally, it is difficult to develop high selective inhibitors (type-II/III inhibitors) because many kinases cannot assume a specific binding site.
Now, Yangbo Feng and his colleagues find a cunning way to settle this problem. They design a bidentate-binding inhibitor that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of wortmannin inhibitor which combine the advantages of both type-I inhibitors (for easy access to kinase inhibitors with high affinity) and type-II/III inhibitors (for high selectivity). More over it bounds to both JNK and LRRK2 (a dual inhibitor) due to its specific design, both of which are associated with Parkinsons disease (PD)

I note that the compound is more like two active compounds which are linked by a linker chain. So we can develop a dual inhibitor for to two related targets in this way which Cediranib is preferred over combined, two individual inhibitors because it eliminates complications of drug drug interactions and the need to optimize individual inhibitor doses for efficacy.

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PI3K