{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:22:22Z","timestamp":1787822542985,"version":"build-2784847793"},"reference-count":90,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"DOI":"10.1038\/s41467-026-76337-2","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:03:40Z","timestamp":1787821420000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Small-molecule RAS\/RAF inhibitors target RAS-driven cancers via allosteric RAF disruption"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1234-0884","authenticated-orcid":false,"given":"Yoko","family":"Yoshikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9329-6362","authenticated-orcid":false,"given":"Shigeyuki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiteru","family":"Makino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kawamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8778-8261","authenticated-orcid":false,"given":"Hitomi","family":"Yuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8544-1187","authenticated-orcid":false,"given":"Naoki","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Shibaike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Okamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wakako","family":"Fujimoto-Sakisaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1904-2736","authenticated-orcid":false,"given":"Kou","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisuke","family":"Horikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morihito","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Horikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4809-2552","authenticated-orcid":false,"given":"Kazumasa","family":"Horie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiyo","family":"Koyanagi-Aoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Aoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5450-3840","authenticated-orcid":false,"given":"Tohru","family":"Kataoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyo","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8238-8851","authenticated-orcid":false,"given":"Atsuo","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruki","family":"Honma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9289-1557","authenticated-orcid":false,"given":"Takashi","family":"Kumasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4134-4286","authenticated-orcid":false,"given":"Hiroo","family":"Koyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumi","family":"Shima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"76337_CR1","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1126\/science.1062023","volume":"294","author":"IR Vetter","year":"2001","unstructured":"Vetter, I. R. & Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 1299\u20131304 (2001).","journal-title":"Science"},{"key":"76337_CR2","doi-asserted-by":"publisher","first-page":"517531","DOI":"10.1038\/nrm2438","volume":"9","author":"AE Karnoub","year":"2008","unstructured":"Karnoub, A. E. & Weinberg, R. A. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell Biol. 9, 517531 (2008).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"76337_CR3","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1038\/s41571-018-0105-0","volume":"15","author":"MB Ryan","year":"2018","unstructured":"Ryan, M. B. & Corcoran, R. B. Therapeutic strategies to target RAS-mutant cancers. Nat. Rev. Clin. Oncol. 15, 709\u2013720 (2018).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"76337_CR4","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.cell.2017.06.009","volume":"170","author":"DK Simanshu","year":"2017","unstructured":"Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17\u201333 (2017).","journal-title":"Cell"},{"key":"76337_CR5","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/j.ccr.2014.02.017","volume":"25","author":"AG Stephen","year":"2014","unstructured":"Stephen, A. G., Esposito, D., Bagni, R. K. & McCormick, F. Dragging ras back in the ring. Cancer Cell 25, 272\u2013281 (2014).","journal-title":"Cancer Cell"},{"key":"76337_CR6","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1038\/d41573-019-00195-5","volume":"18","author":"A Mullard","year":"2019","unstructured":"Mullard, A. Cracking Kras. Nat. Rev. Drug Discov. 18, 887\u2013891 (2019).","journal-title":"Nat. Rev. Drug Discov."},{"key":"76337_CR7","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41587-019-0382-x","volume":"38","author":"C Sheridan","year":"2020","unstructured":"Sheridan, C. Grail of RAS cancer drugs within reach. Nat. Biotech. 38, 6\u20138 (2020).","journal-title":"Nat. Biotech."},{"key":"76337_CR8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41392-020-00451-w","volume":"6","author":"L Huang","year":"2021","unstructured":"Huang, L., Guo, Z., Wang, F. & Fu, L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct. Target Ther. 6, 1\u201320 (2021).","journal-title":"Signal Transduct. Target Ther."},{"key":"76337_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12943-021-01422-7","volume":"20","author":"D Tang","year":"2021","unstructured":"Tang, D., Kroemer, G. & Kang, R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol. Cancer 20, 1\u201324 (2021).","journal-title":"Mol. Cancer"},{"key":"76337_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01274-0","volume":"8","author":"T Jin","year":"2017","unstructured":"Jin, T. et al. RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition. Nat. Commun. 8, 1211 (2017).","journal-title":"Nat. Commun."},{"key":"76337_CR11","doi-asserted-by":"publisher","first-page":"4370","DOI":"10.1038\/s41467-020-18123-2","volume":"11","author":"XM Cotto-Rios","year":"2020","unstructured":"Cotto-Rios, X. M. et al. Inhibitors of BRAF dimers using an allosteric site. Nat. Commun. 11, 4370\u20134385 (2020).","journal-title":"Nat. Commun."},{"key":"76337_CR12","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.str.2014.12.017","volume":"23","author":"SK Fetics","year":"2015","unstructured":"Fetics, S. K. et al. Allosteric effects of the oncogenic RASQ61L mutant on raf-RBD. Structure 23, 505\u2013516 (2015).","journal-title":"Structure"},{"key":"76337_CR13","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nrc.2017.79","volume":"7","author":"Z Karoulia","year":"2017","unstructured":"Karoulia, Z., Gavathiotis, E. & Poulikakos, P. I. New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 7, 676\u2013691 (2017).","journal-title":"Nat. Rev. Cancer"},{"key":"76337_CR14","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/nature12796","volume":"503","author":"JM Ostrem","year":"2013","unstructured":"Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548\u2013551 (2013).","journal-title":"Nature"},{"key":"76337_CR15","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/s41586-019-1694-1","volume":"575","author":"J Canon","year":"2019","unstructured":"Canon, J. et al. The clinical KRAS (G12C) inhibitor AMG510 drives anti-tumor immunity. Nature 575, 217\u2013223 (2019).","journal-title":"Nature"},{"key":"76337_CR16","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1158\/2159-8290.CD-19-1167","volume":"10","author":"J Hallin","year":"2020","unstructured":"Hallin, J. et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54\u201371 (2020).","journal-title":"Cancer Discov."},{"key":"76337_CR17","doi-asserted-by":"publisher","first-page":"2171","DOI":"10.1038\/s41591-022-02007-7","volume":"28","author":"J Hallin","year":"2022","unstructured":"Hallin, J. et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor. Nat. Med. 28, 2171\u20132182 (2022).","journal-title":"Nat. Med."},{"key":"76337_CR18","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/s41586-023-06123-3","volume":"619","author":"D Kim","year":"2023","unstructured":"Kim, D. et al. Pan-KRAS inhibitor disables oncogenic signalling and tumor growth. Nature 619, 160\u2013166 (2023).","journal-title":"Nature"},{"key":"76337_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1158\/2159-8290.CD-24-0027","volume":"14","author":"J Jiang","year":"2024","unstructured":"Jiang, J. et al. Translational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers. Cancer Discov. 14, 1\u201324 (2024).","journal-title":"Cancer Discov."},{"key":"76337_CR20","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1038\/s41586-024-07205-6","volume":"629","author":"M Holderfield","year":"2024","unstructured":"Holderfield, M. et al. Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature 629, 919\u2013926 (2024).","journal-title":"Nature"},{"key":"76337_CR21","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/s41586-024-07379-z","volume":"629","author":"UN Wasko","year":"2024","unstructured":"Wasko, U. N. et al. Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature 629, 927\u2013936 (2024).","journal-title":"Nature"},{"key":"76337_CR22","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/s41571-022-00671-9","volume":"19","author":"SR Punekar","year":"2022","unstructured":"Punekar, S. R., Velcheti, V., Neel, B. G. & Wong, K.-K. The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol. 19, 637\u2013655 (2022).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"76337_CR23","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","volume":"384","author":"MM Awad","year":"2021","unstructured":"Awad, M. M. et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N. Engl. J. Med. 384, 2382\u20132393 (2021).","journal-title":"N. Engl. J. Med."},{"key":"76337_CR24","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/s41586-021-04065-2","volume":"599","author":"Y Zhao","year":"2021","unstructured":"Zhao, Y. et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature 599, 679\u2013683 (2021).","journal-title":"Nature"},{"key":"76337_CR25","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ejca.2021.10.003","volume":"159","author":"CSL Ho","year":"2021","unstructured":"Ho, C. S. L. et al. HER2 mediates clinical resistance to the KRAS(G12C) inhibitor sotorasib, which is overcome by co-targeting SHP2. Eur. J. Cancer 159, 16\u201323 (2021).","journal-title":"Eur. J. Cancer"},{"key":"76337_CR26","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1158\/1078-0432.CCR-19-3523","volume":"26","author":"MB Ryan","year":"2020","unstructured":"Ryan, M. B. et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS (G12C) inhibition. Clin. Cancer Res. 26, 1633\u20131643 (2020).","journal-title":"Clin. Cancer Res."},{"key":"76337_CR27","doi-asserted-by":"publisher","first-page":"e0185862","DOI":"10.1371\/journal.pone.0185862","volume":"12","author":"M Merchant","year":"2017","unstructured":"Merchant, M. et al. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors. PloS One 12, e0185862 (2017).","journal-title":"PloS One"},{"key":"76337_CR28","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.ccr.2010.10.031","volume":"19","author":"S Chandarlapaty","year":"2011","unstructured":"Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58\u201371 (2011).","journal-title":"Cancer Cell"},{"key":"76337_CR29","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1158\/1078-0432.CCR-18-0368","volume":"25","author":"S Misale","year":"2019","unstructured":"Misale, S. et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin. Cancer Res. 25, 796\u2013807 (2019).","journal-title":"Clin. Cancer Res."},{"key":"76337_CR30","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1515\/hsz-2019-0330","volume":"401","author":"G Raphael","year":"2019","unstructured":"Raphael, G. & Wittinghofer, F. The Ras switch in structural and historical perspective. Biol. Chem. 401, 143\u2013163 (2019).","journal-title":"Biol. Chem."},{"key":"76337_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-021-21422-x","volume":"12","author":"TH Tran","year":"2021","unstructured":"Tran, T. H. et al. KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation. Nat. Commun. 12, 1\u201316 (2021).","journal-title":"Nat. Commun."},{"key":"76337_CR32","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1006\/jmbi.1998.2472","volume":"286","author":"T Terada","year":"1999","unstructured":"Terada, T. et al. Nuclear magnetic resonance and molecular dynamics studies on the interactions of the Ras-binding domain of Raf-1 with wild-type and mutant Ras proteins. J. Mol. Biol. 286, 219\u2013232 (1999).","journal-title":"J. Mol. Biol."},{"key":"76337_CR33","doi-asserted-by":"publisher","first-page":"8182","DOI":"10.1073\/pnas.1217730110","volume":"110","author":"F Shima","year":"2013","unstructured":"Shima, F. et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc. Natl. Acad. Sci. USA 110, 8182\u20138187 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"76337_CR34","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1021\/ci700085q","volume":"48","author":"Y Fujiwara","year":"2008","unstructured":"Fujiwara, Y. et al. Virtual screening system for finding structurally diverse hits by active learning. J. Chem. Inf. Model. 48, 930\u2013940 (2008).","journal-title":"J. Chem. Inf. Model."},{"key":"76337_CR35","doi-asserted-by":"publisher","first-page":"2959","DOI":"10.1038\/sj.onc.1201582","volume":"15","author":"M Tamada","year":"1997","unstructured":"Tamada, M., Hu, C. D., Kariya, K., Okada, T. & Kataoka, T. Membrane recruitment of Raf-1 is not the only function of Ras in Raf-1 activation. Oncogene 15, 2959\u20132964 (1997).","journal-title":"Oncogene"},{"key":"76337_CR36","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1158\/2159-8290.CD-17-0321","volume":"8","author":"MT Chang","year":"2018","unstructured":"Chang, M. T. et al. Accelerating discovery of functional mutant alleles in cancer. Cancer Discov. 8, 174\u2013183 (2018).","journal-title":"Cancer Discov."},{"key":"76337_CR37","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1038\/ng.2760","volume":"45","author":"TI Zack","year":"2013","unstructured":"Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134\u20131140 (2013).","journal-title":"Nat. Genet."},{"key":"76337_CR38","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1038\/nrd3845","volume":"11","author":"J Bowes","year":"2012","unstructured":"Bowes, J. et al. Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat. Rev. Drug Discov. 11, 909\u2013922 (2012).","journal-title":"Nat. Rev. Drug Discov."},{"key":"76337_CR39","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/nature00766","volume":"417","author":"H Davis","year":"2002","unstructured":"Davis, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949\u2013954 (2002).","journal-title":"Nature"},{"key":"76337_CR40","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nrc3829","volume":"14","author":"JM Argil\u00e9s","year":"2014","unstructured":"Argil\u00e9s, J. M., Busquets, S., Stemmler, B. & L\u00f3pez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754\u2013762 (2014).","journal-title":"Nat. Rev. Cancer"},{"key":"76337_CR41","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1158\/2159-8290.CD-20-0142","volume":"11","author":"MH Hofmann","year":"2021","unstructured":"Hofmann, M. H. et al. BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 11, 142\u2013157 (2021).","journal-title":"Cancer Discov."},{"key":"76337_CR42","doi-asserted-by":"publisher","first-page":"2551","DOI":"10.1073\/pnas.1812963116","volume":"116","author":"RC Hillig","year":"2019","unstructured":"Hillig, R. C. et al. Discovery of potent SOS1 inhibitors that block Ras activation via disruption of the RAS-SOS1 interaction. Proc. Natl. Acad. Sci. USA 116, 2551\u20132560 (2019).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"76337_CR43","doi-asserted-by":"publisher","first-page":"13578","DOI":"10.1021\/acs.jmedchem.0c01170","volume":"63","author":"MJ LaMarche","year":"2020","unstructured":"LaMarche, M. J. et al. Identification of TNO155, an allosteric SHP2 inhibitor for the treatment of cancer. J. Med Chem. 63, 13578\u201313594 (2020).","journal-title":"J. Med Chem."},{"key":"76337_CR44","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.cell.2016.03.045","volume":"165","author":"SK Athuluri-Divakar","year":"2016","unstructured":"Athuluri-Divakar, S. K. et al. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell 165, 643\u2013655 (2016).","journal-title":"Cell"},{"key":"76337_CR45","doi-asserted-by":"publisher","first-page":"14398","DOI":"10.1073\/pnas.222222699","volume":"99","author":"J Kato-Stankiewicz","year":"2002","unstructured":"Kato-Stankiewicz, J. et al. Inhibitors of Ras\/Raf-1 interaction identified by two-hybrid screening revert Ras-dependent transformation phenotypes in human cancer cells. Proc. Natl. Acad. Sci. USA 99, 14398\u201314403 (2002).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"76337_CR46","doi-asserted-by":"publisher","first-page":"4756","DOI":"10.1039\/C7SC00311K","volume":"8","author":"L-J Liu","year":"2017","unstructured":"Liu, L.-J. et al. Inhibition of the Ras\/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(iii) metal-based compound. Chem. Sci. 8, 4756\u20134763 (2017).","journal-title":"Chem. Sci."},{"key":"76337_CR47","doi-asserted-by":"publisher","first-page":"e0125021","DOI":"10.1371\/journal.pone.0125021","volume":"10","author":"JC Uitdehaag","year":"2015","unstructured":"Uitdehaag, J. C. et al. Selective targeting of CTNNB1-, KRAS- or MYC-driven cell growth by combinations of existing drugs. PloS One 10, e0125021 (2015).","journal-title":"PloS One"},{"key":"76337_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32157-8","volume":"13","author":"A Li","year":"2022","unstructured":"Li, A. et al. Cytosine base editing systems with minimized off-target effect and molecular size. Nat. Commun. 13, 4531 (2022).","journal-title":"Nat. Commun."},{"key":"76337_CR49","doi-asserted-by":"publisher","first-page":"236","DOI":"10.3390\/biom11020236","volume":"11","author":"C Kiel","year":"2021","unstructured":"Kiel, C., Matallanas, D. & Kolch, W. The Ins and Outs of RAS Effector Complexes. Biomolecules 11, 236\u2013263 (2021).","journal-title":"Biomolecules"},{"key":"76337_CR50","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.bbrc.2008.01.169","volume":"369","author":"J Liao","year":"2008","unstructured":"Liao, J. et al. Two conformational states of Ras GTPase exhibit differential GTP-binding kinetics. Biochem. Biophys. Res. Commun. 369, 327\u2013332 (2008).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"76337_CR51","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/0009-2614(80)80041-8","volume":"69","author":"G Bodenhausen","year":"1980","unstructured":"Bodenhausen, G. & Ruben, D. J. Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy. Chem. Phys. Lett. 69, 185\u2013189 (1980).","journal-title":"Chem. Phys. Lett."},{"key":"76337_CR52","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1006\/jmrb.1995.1109","volume":"108","author":"S Mori","year":"1995","unstructured":"Mori, S., Abeygunawardana, C., Johnson, M. O. & Vanzijl, P. C. M. Improved sensitivity of HSQC spectra of exchanging protons at short interscan delays using a new fast HSQC (FHSQC) detection scheme that avoids water saturation. J. Magn. Reson. Ser. B 108, 94\u201398 (1995).","journal-title":"J. Magn. Reson. Ser. B"},{"key":"76337_CR53","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1007\/BF02192855","volume":"2","author":"M Piotto","year":"1992","unstructured":"Piotto, M., Saudek, V. & Sklen\u00e1\u0159, V. Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions. J. Biomol. NMR 2, 661\u2013665 (1992).","journal-title":"J. Biomol. NMR"},{"key":"76337_CR54","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1006\/jmra.1993.1098","volume":"102","author":"V Sklenar","year":"1993","unstructured":"Sklenar, V., Piotto, M., Leppik, R. & Saudek, V. Gradient-tailored water suppression for 1H-15N HSQC experiments optimized to retain full sensitivity. J. Magn. Reson., Ser. A 102, 241\u2013245 (1993).","journal-title":"J. Magn. Reson., Ser. A"},{"key":"76337_CR55","doi-asserted-by":"publisher","DOI":"10.1007\/BF00178261","author":"S Grzesiek","year":"1993","unstructured":"Grzesiek, S. & Bax, A. Amino acid type determination in the sequential assignment procedure of uniformly 13C\/15N-enriched proteins. J. Biomol. NMR https:\/\/doi.org\/10.1007\/BF00178261 (1993).","journal-title":"J. Biomol. NMR"},{"key":"76337_CR56","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1006\/jmrb.1994.1032","volume":"103","author":"DR Muhandiram","year":"1994","unstructured":"Muhandiram, D. R. & Kay, L. E. Gradient-enhanced triple-resonance three-dimensional NMR experiments with improved sensitivity. J. Magn. Reson., Ser. B 103, 203\u2013216 (1994).","journal-title":"J. Magn. Reson., Ser. B"},{"key":"76337_CR57","first-page":"432","volume":"96","author":"S Grzesiek","year":"1992","unstructured":"Grzesiek, S. & Bax, A. Improved 3D triple-resonance NMR techniques applied to a 31 kDa protein. J. Magn. Reson. 96, 432\u2013440 (1992).","journal-title":"J. Magn. Reson."},{"key":"76337_CR58","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1006\/jmra.1994.1145","volume":"109","author":"LE Kay","year":"1994","unstructured":"Kay, L. E., Xu, G. Y. & Yamazaki, T. Enhanced-sensitivity triple-resonance spectroscopy with minimal H2O saturation. J. Magn. Reson., Ser. A 109, 129\u2013133 (1994).","journal-title":"J. Magn. Reson., Ser. A"},{"key":"76337_CR59","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1002\/anie.199314891","volume":"32","author":"J Schleucher","year":"1993","unstructured":"Schleucher, J., Sattler, M. & Griesinger, C. Coherence selection by gradients without signal attenuation: application to the three-dimensional HNCO experiment. Angew. Chem. Int. Ed. Engl. 32, 1489\u20131491 (1993).","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"76337_CR60","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1006\/jmre.2001.2374","volume":"151","author":"A Meissner","year":"2001","unstructured":"Meissner, A. & S\u00f8rensen, O. W. Sequential HNCACB and CBCANH protein NMR pulse sequences. J. Magn. Reson. 151, 328\u2013331 (2001).","journal-title":"J. Magn. Reson."},{"key":"76337_CR61","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/0022-2364(92)90252-3","volume":"97","author":"RT Clubb","year":"1992","unstructured":"Clubb, R. T. A constant-time three-dimensional Tripk4Wmnan ce pulse scheme to correlate intraresidue \u2018H N, 15N, and 13C\u2019chemical shifts in \u201cN- 13C-labeled proteins. J. Magn. Reson. (1969) 97, 213\u2013217 (1992).","journal-title":"J. Magn. Reson. (1969)"},{"key":"76337_CR62","doi-asserted-by":"publisher","first-page":"10663","DOI":"10.1021\/ja00052a088","volume":"114","author":"L Kay","year":"1992","unstructured":"Kay, L., Keifer, P. & Saarinen, T. Pure absorption gradient enhanced heteronuclear single quantum correlation spectroscopy with improved sensitivity. J. Am. Chem. Soc. 114, 10663\u201310665 (1992).","journal-title":"J. Am. Chem. Soc."},{"key":"76337_CR63","first-page":"151","volume":"93","author":"AG Palmer","year":"1991","unstructured":"Palmer, A. G., Cavanagh, J., Wright, P. E. & Rance, M. Sensitivity improvement in proton-detected two-dimensional heteronuclear correlation NMR spectroscopy. J. Magn. Reson. 93, 151\u2013170 (1991).","journal-title":"J. Magn. Reson."},{"key":"76337_CR64","doi-asserted-by":"publisher","DOI":"10.1007\/BF00175254","author":"J Schleucher","year":"1994","unstructured":"Schleucher, J. et al. A general enhancement scheme in heteronuclear multidimensional NMR employing pulsed field gradients. J. Biomol. NMR https:\/\/doi.org\/10.1007\/BF00175254 (1994).","journal-title":"J. Biomol. NMR"},{"key":"76337_CR65","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1006\/jmrb.1993.1053","volume":"101","author":"LE Kay","year":"1993","unstructured":"Kay, L. E., Xu, G. Y., Singer, A. U., Muhandiram, D. R. & Formankay, J. D. A gradient-enhanced HCCH-TOCSY experiment for recording side-chain 1H and 13C correlations in H2O samples of proteins. J. Magn. Reson. Ser. B. 101, 333\u2013337 (1993).","journal-title":"J. Magn. Reson. Ser. B."},{"key":"76337_CR66","doi-asserted-by":"publisher","unstructured":"Forman-Kay, J. D. et al. Structural, Dynamic, and Folding Studies of SH2 and SH3 Domains. in NMR as a Structural Tool for Macromolecules: Current Status and Future Directions (Rao, B. D. N., and Kemple, M. D. eds), pp. 35\u201347, Springer US, Boston, MA, https:\/\/doi.org\/10.1007\/978-1-4613-0387-9_3 (1996).","DOI":"10.1007\/978-1-4613-0387-9_3"},{"key":"76337_CR67","first-page":"207","volume":"98","author":"AL Davis","year":"1992","unstructured":"Davis, A. L., Keeler, J., Laue, E. D. & Moskau, D. Experiments for recording pure-absorption heteronuclear correlation spectra using pulsed field gradients. J. Magn. Reson. 98, 207\u2013216 (1992).","journal-title":"J. Magn. Reson."},{"key":"76337_CR68","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1007\/BF00197809","volume":"6","author":"F Delaglio","year":"1995","unstructured":"Delaglio, F. et al. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR 6, 277\u2013293 (1995).","journal-title":"J. Biomol. NMR"},{"key":"76337_CR69","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s10858-007-9175-5","volume":"39","author":"N Kobayashi","year":"2007","unstructured":"Kobayashi, N. et al. KUJIRA, a package of integrated modules for systematic and interactive analysis of NMR data directed to high-throughput NMR structure studies. J. Biomol. NMR 39, 31\u201352 (2007).","journal-title":"J. Biomol. NMR"},{"key":"76337_CR70","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s10858-012-9641-6","volume":"53","author":"N Kobayashi","year":"2012","unstructured":"Kobayashi, N. et al. An automated system designed for large scale NMR data deposition and annotation: Application to over 600 assigned chemical shift data entries to the BioMagResBank from the RIKEN Structural Genomics\/Proteomics Initiative internal database. J. Biomol. NMR 53, 311\u2013320 (2012).","journal-title":"J. Biomol. NMR"},{"key":"76337_CR71","doi-asserted-by":"publisher","first-page":"12817","DOI":"10.1021\/ja305091n","volume":"134","author":"E Schmidt","year":"2012","unstructured":"Schmidt, E. & G\u00fcntert, P. A new algorithm for reliable and general NMR resonance assignment. J. Am. Chem. Soc. 134, 12817\u201312829 (2012).","journal-title":"J. Am. Chem. Soc."},{"key":"76337_CR72","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1006\/jmbi.1997.1284","volume":"273","author":"P G\u00fcntert","year":"1997","unstructured":"G\u00fcntert, P., Mumenthaler, C. & W\u00fcthrich, K. Torsion angle dynamics for NMR structure calculation with the new program DYANA. J. Mol. Biol. 273, 283\u2013298 (1997).","journal-title":"J. Mol. Biol."},{"key":"76337_CR73","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/S0022-2836(02)00241-3","volume":"319","author":"T Herrmann","year":"2002","unstructured":"Herrmann, T., G\u00fcntert, P. & W\u00fcthrich, K. Protein NMR structure determination with automated NOE assignment using the new software CANDID and the torsion angle dynamics algorithm DYANA. J. Mol. Biol. 319, 209\u2013227 (2002).","journal-title":"J. Mol. Biol."},{"key":"76337_CR74","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1107\/S0907444998003254","volume":"54","author":"AT Br\u00fcnger","year":"1998","unstructured":"Br\u00fcnger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. Sect. D. Biol. Crystallogr. 54, 905\u2013921 (1998).","journal-title":"Acta Crystallogr. Sect. D. Biol. Crystallogr."},{"key":"76337_CR75","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera-a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."},{"key":"76337_CR76","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1107\/S0907444909047337","volume":"66","author":"W.XDS. Kabsch","year":"2010","unstructured":"Kabsch, W. X. D. S. Acta Crystallogr. D. Biol. Crystallogr. 66, 125\u2013132 (2010).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"76337_CR77","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1107\/S0021889807021206","volume":"40","author":"AJ McCoy","year":"2007","unstructured":"McCoy, A. J. et al. Phaser crystallographic software. J. Appl Crystallogr 40, 658\u2013674 (2007).","journal-title":"J. Appl Crystallogr"},{"key":"76337_CR78","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1107\/S2059798319011471","volume":"75","author":"D Liebschner","year":"2019","unstructured":"Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons, and electrons: recent developments in Phenix. Acta Crystallogr D. Struct. Biol. 75, 861\u2013877 (2019).","journal-title":"Acta Crystallogr D. Struct. Biol."},{"key":"76337_CR79","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1107\/S0907444912001308","volume":"68","author":"PV Afonine","year":"2012","unstructured":"Afonine, P. V. et al. Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr. D. Biol. Crystallogr. 68, 352\u2013367 (2012).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"76337_CR80","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","volume":"66","author":"P Emsley","year":"2010","unstructured":"Emsley, P., Lohkamp, B., Scott, W. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486\u2013501 (2010).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"76337_CR81","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1107\/S090744491200251X","volume":"68","author":"AA Lebedev","year":"2012","unstructured":"Lebedev, A. A. et al. Jligand: a graphical tool for the CCP4 template-restraint library. Acta Crystallogr. D. Biol. Crystallogr. 68, 431\u2013440 (2012).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"76337_CR82","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1107\/S0907444910045749","volume":"67","author":"MD Winn","year":"2011","unstructured":"Winn, M. D. et al. Overview of the CCP4 suite and current development. Acta Crystallogr. D. Biol. Crystallogr. 67, 235\u2013242 (2011).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"76337_CR83","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","volume":"66","author":"VB Chen","year":"2010","unstructured":"Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D. Biol. Crystallogr. 66, 12\u201321 (2010).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"76337_CR84","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1107\/S0021889812017293","volume":"45","author":"N Echols","year":"2012","unstructured":"Echols, N. et al. Graphical tools for macromolecular crystallography in PHENIX. J. Appl Crystallogr 45, 581\u2013586 (2012).","journal-title":"J. Appl Crystallogr"},{"key":"76337_CR85","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1107\/S2059798318017795","volume":"75","author":"K Hirata","year":"2019","unstructured":"Hirata, K. et al. ZOO: an automatic data-collection system for high-throughput structure analysis in protein microcrystallography. Acta Crystallogr. Sect. D: Struct. Biol. 75, 138\u2013150 (2019).","journal-title":"Acta Crystallogr. Sect. D: Struct. Biol."},{"key":"76337_CR86","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1107\/S2059798318004576","volume":"74","author":"K Yamashita","year":"2018","unstructured":"Yamashita, K. et al. KAMO: towards automated data processing for microcrystals. Acta Crystallogr. Sect. D: Struct. Biol. 74, 441\u2013449 (2018).","journal-title":"Acta Crystallogr. Sect. D: Struct. Biol."},{"key":"76337_CR87","first-page":"355","volume":"D67","author":"GN Murshudov","year":"2011","unstructured":"Murshudov, G. N. et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta Cryst. D67, 355\u2013367 (2011).","journal-title":"Acta Cryst."},{"key":"76337_CR88","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/j.stem.2016.04.003","volume":"18","author":"M Fujii","year":"2016","unstructured":"Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18, 827\u2013838 (2016).","journal-title":"Cell Stem Cell"},{"key":"76337_CR89","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.stem.2018.11.016","volume":"23","author":"M Fujii","year":"2018","unstructured":"Fujii, M. et al. Human intestinal organoids maintain self-renewal capacity and cellular diversity in niche-inspired culture condition. Cell Stem Cell 23, 787\u2013793.e6 (2018).","journal-title":"Cell Stem Cell"},{"key":"76337_CR90","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1038\/s41589-022-00984-x","volume":"18","author":"K Toshimitsu","year":"2022","unstructured":"Toshimitsu, K. et al. Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer. Nat. Chem. Biol. 18, 605\u2013614 (2022).","journal-title":"Nat. Chem. Biol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76337-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76337-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76337-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:03:42Z","timestamp":1787821422000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76337-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":90,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["76337"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-76337-2","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"assertion":[{"value":"17 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"8809"}}