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. 2024 Apr 24;629(8011):443–449. doi: 10.1038/s41586-024-07350-y

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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. 4 — a, The therapeutic response to HRO761 in mice bearing SW48 xenografts. Mice were treated for 92 days with vehicle (n = 5) or HRO761 (orally, once daily) at doses up to 120 mg per kg. Mouse body weight was measured from the treatment start. Data are mean ± s.e.m. b, Free HRO761 blood concentrations (n = 3) at day 7 and 91 (mouse unbound faction = 19.3%) (left); unbound GI₉₀ (0.16 µM and in vitro unbound fraction = 37%) is represented as a dotted line. Right, the correlation between efficacy and unbound blood area under the curve (AUC_b,u) above the SW48 cell unbound GI₉₀. Data are mean ± s.e.m. (left). c, Immunoblot analysis of WRN, pATM (Ser1981), pCHK2 (Thr68), total CHK2, pKAP1, p21 and actin from SW48-tumour bearing mice (n = 3) treated daily with 20 and 60 mg per kg and euthanized and sampled 4 h after the last treatment from day 1 to day 21 (top). Bottom, CDKN1A, GDF15, CENPA and KIF20A mRNA levels were quantified by RT–qPCR. Data are mean ± s.e.m. percentage expression compared with the DMSO control group. d, WRN and pCHK2 expression were evaluated on SW48 xenograft FFPE sections using immunohistochemistry. Scale bars, 50 µm. Replicate information is provided in the ‘Statistics and reproducibility’ section of the Methods. e, Best average response from multiple MSI xenograft models (n = 5–7) after treatment with HRO761 at 60 or 120 mg per kg according to the model. f, Incucyte-generated confluence plots from SW48 cells exposed to a combination of HRO761 and irinotecan (irinot.) at the indicated concentrations. The graph is a representative experiment of n = 3 experiments. g, SW48 tumour xenograft growth of mice (n = 5–6) treated with HRO761 at 20 mg per kg, irinotecan (intravenous, weekly) or a combination of HRO761 with a decreasing dose of irinotecan from 60 to 15 mg per kg (left), or HRO761 at 40 mg per kg or a combination of HRO761 with a decreasing dose of irinotecan from 15 to 5 mg per kg (right). Data are mean ± s.e.m.

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