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Deepening understanding of how Bcl-2 family proteins protect cancer cells from apoptosis has driven the development of 'BH3 mimetic' drugs that target various anti-apoptotic Bcl-2-like proteins by mimicking their natural inhibitors, the BH3-only proteins. The proof of target engagement and an on-target mechanism validation are critical for evaluating drug development potential. To evaluate target engagement of BH3 mimetics in cells, we measured binding potency of ABT-199, A-1210477 and ABT-737 to Bcl-2 and Mcl-1 proteins by using a dose-response cellular thermal shift assay (CETSA), similar affinity rank-order and selectivity were obtained in comparison with in vitro binding assays. A proof of direct target engagement for S1 and AT-101 was obtained through CETSA assay. By using a previously established mathematical model, we simulated individual death response of various cancer cell lines to ABT-199, S1 or AT-101 in comparison with experimental data. A positive correlation between model predictions and experimental data for ABT-199 and S1 showed that dual Bcl-2 and Mcl-1 target engagement underlies their anticancer efficacy. In contrast, an off-target effect was determined for AT-101.
Pubmed ID: 31669390
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Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.
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