Using CETSA assay and a mathematical model to reveal dual Bcl-2/Mcl-1 inhibition and on-target mechanism for ABT-199 and S1
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-tar...
Saved in:
Published in | European journal of pharmaceutical sciences Vol. 142; p. 105105 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
15.01.2020
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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.
[Display omitted] |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0928-0987 1879-0720 |
DOI: | 10.1016/j.ejps.2019.105105 |