Small-molecule RAS/RAF inhibitors target RAS-driven cancers via allosteric RAF disruption

RAS, a frequently mutated cancer-driver gene, has been the focus of intensive research, with numerous inhibitors developed to target RAS and its signalling molecules. With the advent of approved subtype-specific RAS inhibitors targeting KRASG12C mutation, the development of RAS inhibitors that are effective regardless of RAS mutation status is the next major challenge to address clinically prevalent RAS mutations and further overcome RAS-driven acquired resistance to currently available drugs. With the goal of obtaining broad-spectrum aberrant RAS-signalling inhibitors, we conduct multimodule drug screening for small-molecule compounds capable of RAS/RAF-binding inhibition. Structural studies of the hit compounds demonstrate that they covalently bind to a distinct site in the RAS-binding domain of RAF and allosterically disrupt RAF conformation, thereby preventing RAS/RAF interaction and downstream signalling. The compounds exhibit antitumour efficacy against multiple cancers with varying RAS mutations, including KRAS, NRAS and HRAS, and wild-type RAS-driven cancers in preclinical models. Furthermore, they effectively suppress tumour growth of BRAFV600E-melanoma with acquired BRAF inhibitor resistance by preventing RAS signal reactivation. These findings provide a possible approach for designing RAF-targeting compounds, and the resulting molecules may serve as the basis for developing RAS/RAF-signalling inhibitors with distinct mechanisms to overcome multiple RAS-driven cancers.

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Publication Details

Journal
Nature Communications
Published
2026-08-27
DOI
https://doi.org/10.1038/s41467-026-76337-2
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

Small-molecule RAS/RAF inhibitors target RAS-driven cancers via allosteric RAF disruption

Yoko Yoshikawa, Takashi Kumasaka, Manabu Horikawa, Hitomi Yuki et al.
Nature Communications
Melanoma and MAPK Pathways
article

Small-molecule RAS/RAF inhibitors target RAS-driven cancers via allosteric RAF disruption

Yoko Yoshikawa, Takashi Kumasaka, Manabu Horikawa, Hitomi Yuki, Megumi Okamura, Ichiro Mori, Kazumasa Horie, Shigeyuki Matsumoto, Tohru Kataoka, Takashi Aoi, Atsuo Tamura, Yoshiteru Makino, Michiyo Koyanagi‐Aoi, Hiroo Koyama, Akira Shibaike, Taisuke Horikawa, Fumi Shima, Takashi Kawamura, Naoki Sakai, Tomoyo Okada, Kou Honda, Wakako Fujimoto-Sakisaka, Teruki Honma, Morihito Okada, Hirokazu Kubota
article en

Abstract

RAS, a frequently mutated cancer-driver gene, has been the focus of intensive research, with numerous inhibitors developed to target RAS and its signalling molecules. With the advent of approved subtype-specific RAS inhibitors targeting KRASG12C mutation, the development of RAS inhibitors that are effective regardless of RAS mutation status is the next major challenge to address clinically prevalent RAS mutations and further overcome RAS-driven acquired resistance to currently available drugs. With the goal of obtaining broad-spectrum aberrant RAS-signalling inhibitors, we conduct multimodule drug screening for small-molecule compounds capable of RAS/RAF-binding inhibition. Structural studies of the hit compounds demonstrate that they covalently bind to a distinct site in the RAS-binding domain of RAF and allosterically disrupt RAF conformation, thereby preventing RAS/RAF interaction and downstream signalling. The compounds exhibit antitumour efficacy against multiple cancers with varying RAS mutations, including KRAS, NRAS and HRAS, and wild-type RAS-driven cancers in preclinical models. Furthermore, they effectively suppress tumour growth of BRAFV600E-melanoma with acquired BRAF inhibitor resistance by preventing RAS signal reactivation. These findings provide a possible approach for designing RAF-targeting compounds, and the resulting molecules may serve as the basis for developing RAS/RAF-signalling inhibitors with distinct mechanisms to overcome multiple RAS-driven cancers.

Nature CommunicationsVol. 17(1)
Hiroshima University (JP), Memorial Sloan Kettering Cancer Center (US), Tohoku University (JP), Kyoto University (JP), Kobe University Hospital (JP), RIKEN Center for Sustainable Resource Science (JP), Japanese Red Cross Kobe Hospital (JP), Japan Synchrotron Radiation Research Institute (JP), KAN Research Institute (JP), RIKEN Center for Biosystems Dynamics Research (JP), Kobe University (JP)
Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science
Good health and well-being
Openalex Percentile: Top 17%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
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