Using CETSA assay and a mathematical model to reveal dual Bcl-2/Mcl-1 inhibition and on-target mechanism for ABT-199 and S1
| Autor: | Minhang Zhang, Peng Liu, Xiaodong Zhang, Ting Song, Zuguang Xue, Zongwei Guo, Zhichao Zhang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Thermal shift assay
THP-1 Cells Pharmaceutical Science Antineoplastic Agents Apoptosis HL-60 Cells 02 engineering and technology Positive correlation 030226 pharmacology & pharmacy Jurkat Cells 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Humans Potency Sulfonamides Bh3 mimetics Chemistry Mechanism (biology) Drug Synergism Models Theoretical Bridged Bicyclo Compounds Heterocyclic 021001 nanoscience & nanotechnology Cell biology Proto-Oncogene Proteins c-bcl-2 Drug development Cancer cell MCF-7 Cells Myeloid Cell Leukemia Sequence 1 Protein Biological Assay Apoptosis Regulatory Proteins 0210 nano-technology |
| Zdroj: | European Journal of Pharmaceutical Sciences. 142:105105 |
| ISSN: | 0928-0987 |
| DOI: | 10.1016/j.ejps.2019.105105 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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