https://orcid.org/0000-0003-3556-7931
Figures & data
Figure 1. Altering drug binding rates may be a partial resistance mechanism to kinase inhibition. (a) Kinetic mutations in breakpoint cluster region (BCR)-ABL cause resistance through increased drug binding and dissociation rates, whereas thermodynamic mutations abrogate drug binding. (b) Simulated effect of mutation on compound off-rates in a model system of a patient over 24 h. Threshold for pharmacological inhibition is 50% of target fraction bound. Coloring scheme consistent with panel A.
Alt Text: (a) Three cartoon breakpoint cluster region (BCR)-ABL proteins binding to a spherical cartoon drug with differently sized rate arrows to illustrate wild-type versus a kinetic mutant and a thermodynamic mutant. (b) Simulated effect of mutation on residence time. Three curves plotted with a dotted line representing the fraction of target protein bound necessary for inhibition. Wild-type stays above the dotted line for the full duration, whereas the kinetic mutant stays above the dotted line for only a third of the duration and the thermodynamic mutant never reaches above the line.
