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. 2021 Feb 10;12:920. doi: 10.1038/s41467-021-21159-7

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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. 1 — a Chemical structure of vemurafenib and BRAF targeting PROTAC, SJF-0628, and its epimer, SJF-0661. SJF-0628 is composed of vemurafenib, a short piperazine-based linker, and a VHL recruiting ligand. SJF-0661 has an identical warhead and linker as SJF-0628 but contains an inverted hydroxyl group in the VHL ligand and is therefore unable to engage VHL to induce ubiquitination. b Inducible NIH3T3 cells expressing indicated V5-BRAF constructs (doxycycline 100–200 ng/mL, 24 h) treated with increasing amounts of SJF-0628. c SK-MEL-28 cells (homozygous BRAF^V600E) treated with indicated amounts of SJF-0628 induced BRAF degradation and suppression of MEK and ERK phosphorylation. d Quantitation of ERK inhibition in SK-MEL-28 cells treated with SJF-0628 or SJF-0661 (mean ± SD, n = 3 biologically independent samples) P value calculated by multiple unpaired t-tests. e Quantitation of SJF-0628 treatment time course (100 nM) at indicated times in SK-MEL-28 cells shows maximal degradation within 4 h (n = 2 biologically independent samples). f SJF-0628 induces selective degradation of p61-BRAF^V600E mutant and inhibits MEK and ERK phosphorylation but spares BRAF^WT and CRAF in SK-MEL-239-C4 cells. g H1666 (heterozygous BRAF^G466V) treated with SJF-0628 shows BRAF degradation, but incomplete suppression of ERK signaling. h BRAF^WT is spared by SJF-0628 in OVCAR-8 cells but induces slight activation of ERK phosphorylation. i Covalent inhibition of KRAS^G12C by MRTX849 in H23 cells hinders PROTAC induced BRAF^WT degradation (n = 3 biologically independent samples). j Quantification of 1i (mean ± SD, n = 3 biologically independent samples). P value calculated by one-way ANOVA. Source data are provided as a Source Data file.