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. 2022 Jan 22;9(1):2029999.
doi: 10.1080/23723556.2022.2029999. eCollection 2022.

Resistance to kinase inhibition through shortened target engagement

Aziz M Rangwala  1 , Benedict-Tilman Berger  2   3 , Matthew B Robers  4 , Stefan Knapp  2   3 , Markus A Seeliger  1
Affiliations

Resistance to kinase inhibition through shortened target engagement

Aziz M Rangwala et al. Mol Cell Oncol. .

Abstract

Imatinib, a selective inhibitor of the breakpoint cluster region (BCR)-ABL kinase, is the poster child for targeted cancer therapeutics. However, its efficacy is limited by resistance mutations. Using a quantitative bioluminescence resonance energy transfer assay in living cells, we identified ABL kinase mutations that could cause imatinib resistance by altering drug residence time.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
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.
See this image and copyright information in PMC

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