Design strategies to overcome resistance mutations

The observation that various resistance mutations lead to a drop in inhibitor potency opens the possibility that a simple increase in potency might overcome 

Increasing potency Designing to the active state of the kinase Avoiding interaction with the gatekeeper Nilotinib Dasatinib VX-680, danusertib 

An example of a specifically designed inhibitor is shown with the design of AP-23846 5.17 based on its parent compound AP-23464, 5.18. In this case, the 

A novel alternative to attempting to develop a potent and selective ATP-competitive inhibitor is to target the peptide site of the kinase. This strategy has been applied with the design of ONO-12380 5.20, which is non-competitive to ATP and showed no loss of potency to 16 mutant strains of BCR-Abl.57 

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Table 5.2 Design strategies to overcome resistance mutations in Abl and Kit.

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