The challenge of developing robust drugs to overcome resistance

Abstract

Drug resistance is problematic in microbial disease, viral disease and cancer. Understanding at the outset that resistance will impact the effectiveness of any new drug that is developed for these disease categories is imperative. In this Feature, we detail approaches that have been taken with selected drug targets to reduce the susceptibility of new drugs to resistance mechanisms. We will also define the concepts of robust drugs and resilient targets, and discuss how the design of robust drugs and the selection of resilient targets can lead to successful strategies for combating resistance.

Figure 1

(a) Structures of first- and second-generation BCR-ABL kinase inhibitors. (b) Structures of EGFR tyrosine kinase inhibitors. (c) Structures of PDGFR inhibitors. (d) Inhibitors that target the GyrA/ParA subunit of gyrase and/or TopoIV. (e) Benzimidazole GyrB/ParE inhibitors.

Figure 1

(a) Structures of first- and second-generation BCR-ABL kinase inhibitors. (b) Structures of EGFR tyrosine kinase inhibitors. (c) Structures of PDGFR inhibitors. (d) Inhibitors that target the GyrA/ParA subunit of gyrase and/or TopoIV. (e) Benzimidazole GyrB/ParE inhibitors.

Figure 2. Crystal structures of EGFR (green) with bound inhibitors (purple or magenta)

(a) Erlotinib competes with ATP in the active site of EGFR; (b) HKI272 forms a covalent link with Cys 797 to eliminate the equilibrium between inhibitor and ATP.

Figure 3

Crystal structure of moxifloxicin bound to GyrA [59]

Figure 4

Crystal structure of GSK299423 bound to ParB [62]