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. 2024 Apr 8;629(8013):919–926. doi: 10.1038/s41586-024-07205-6

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© The Author(s) 2024

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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — a,b, Formation of KRAS–CYPA complexes and disruption of the KRAS(G12V)–CRAF interaction in U2OS cells as a time course after 50 nM RMC-7977 treatment, expressed as % of the maximum (max) signal (a), and correlation between potency of RAS–RAF inhibition and formation of the tri-complex for multiple KRAS variants (R² = 0.7) (b). Data points are single nano-BRET measurements representative of three independent experiments. c, Proliferation (measured by CellTiter-Glo (CTG) assay) of NCI-H358 cells with doxycycline (Dox)-inducible expression of low or high CYPA levels treated with RMC-7977 for 120 h. Data points show biological duplicates normalized to vehicle control. Representative data from one of three independent experiments. d, Liquid chromatography–mass spectrometry measurements of the ratio of RMC-7977 concentration in CYPA-high and CYPA-low NCI-H358 cells to the concentration in the medium with 1 h compound treatment. Bars depict the mean of biological triplicates from one of two replicate experiments (P = 0.012, one-way analysis of variance (ANOVA) with post hoc Tukey’s test). e, Western blots of isogenic MEF cells expressing the indicated KRAS variant or BRAF(V600E) and treated with RMC-7977 or DMSO for 24 h. Data are representative of three independent experiments. f,g, pERK (AlphaLISA) (f) and proliferation (CTG assay) (g) levels of human cancer cell lines with G12 (Capan-1, SW620, AsPC-1, HPAC, NCI-H358, PSN1 and HUPT3), G13 (HCT 116) or Q61 (Hs 766T) mutant KRAS; Q61-mutant NRAS (SK-MEL-30 and KU1919); mutant EGFR (NCI-H1975); or BRAF^V600E (A375), treated with RMC-7977 for 4 h. Data points show biological duplicates normalized to vehicle control from 1 of 2–26 independent experiments.

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