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. 2021 Nov 25;12:6896. doi: 10.1038/s41467-021-27210-x

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — a The structure of 753a and 753b. b The potency of 753a and 753b in degrading BCL-xL/2 was evaluated in 293T cells by immunoblots after the cells were treated with different concentrations of 753a or 753b for 16 h. c Comparison of the potencies of 753b and DT2216 in degrading BCL-xL/2 by immunoblots in 293T cells after the cells were treated with different concentrations of 753b or DT2216 for 16 h. d The time course of 753b-mediated BCL-xL/2 degradation was evaluated in 293T cells by immunoblots after the cells were treated with 1 μM 753b for various time points as indicated. Representative immunoblots are shown in (a–d) and β-actin was used as a loading control in all immunoblot analyses. The normalized protein content in the immunoblots is presented as mean values ± s.e.m. (n = 3 biologically independent experiments) in the bar graph (bottom panel). e, f The formation of BCL-xL/PROTAC/VCB (e) and BCL-2/PROTAC/VCB (f) ternary complexes in a cell-free condition was determined by AlphaLISA assay. Data represent the mean of a single experiment with 2 technical replicates. Similar results were obtained in one more independent experiment. g, h NanoBRET assays showed that 753b forms more stable ternary complexes with BCL-xL (g) and BCL-2 (h) in 293T cells compared with 753a. 293T cells were transiently transfected with HiBit-BCL-xL, LgBit, and HaloTag-VHL or HiBit-BCL-2, LgBit, and HaloTag-VHL and then treated with a serial dilution of 753a or 753b for 6 h. Data are expressed as mean of three biological replicates. i The different conformations of linker methyl groups on ABT263 observed in X-ray crystal structure of BCL-xL/ABT263 complex (PDB 4QNQ). Source data are provided as a Source data file.