Daraxonrasib（RMC-6236）是一种非共价、高效的RAS (ON) 抑制剂，可靶向多种RAS突变体及野生型变体。Daraxonrasib通过与细胞内伴侣蛋白Cyclophilin A (CypA)结合形成复合物，再进一步与激活状态的RAS蛋白（GTP结合态）形成三元复合体，从而有效阻断RAS与下游效应蛋白（如RAF）的结合，抑制其信号转导功能。这种机制绕开了传统抑制剂难以结合RAS的问题。
在体外实验中，Daraxonrasib（CAS No.：2765081-21-6）展现出广谱且高效的抑制能力。它能够有效阻断多种RAS突变体（如G12C、G12D、G12V、G13D、Q61H、Q61R等）与下游效应蛋白之间的结合，IC₅₀值最低可达35 nM。在多个携带不同RAS突变的癌细胞系中，Daraxonrasib能显著降低pERK水平（RAS活化的标志物）并抑制细胞增殖，其IC₅₀范围分别为1.08-2.61nM与0.80-27.1nM，表明其对多种RAS突变型肿瘤具有潜在的研究价值[1, 2]。Daraxonrasib在动物实验中以25 mg/kg，口服给药的形式有效抑制了PaCa-2荷瘤小鼠的肿瘤生长[3]。
在胰腺癌的研究中，Daraxonrasib同样以25 mg/kg的剂量结合免疫检查点抑制Anti-mouse PD-1单抗成功限制了胰腺癌在小鼠抑制模型中的增长[4]。Elironrasib（RMC-6291，30 mg/kg）和Daraxonrasib（25 mg/kg）的组合可增加RAS突变型肿瘤对免疫调节剂的敏感性[5]。
参考文献及鸣谢
[1] Khan, H. Y.; Nagasaka, M.; Aboukameel, A.; et al. Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers. Molecular cancer therapeutics2023, 22 (12), 1422-1433.
[2] Liaki, V.; Barrambana, S.; Kostopoulou, M.; et al. A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. Proceedings of the National Academy of Sciences of the United States of America2025, 122 (49), e2523039122.
[3] Ma, Z.; Zhou, M.; Shen, Q.; et al. RAS (ON) Therapies on the Horizon to Address KRAS Resistance: Highlight on a Phase III Clinical Candidate Daraxonrasib (RMC-6236). ACS Publications: 2025; Vol. 68, pp 12287-12292.
[4] Orlen, M. I. RAS Inhibition and Anti-Tumor Immunity in Pancreatic Cancer. University of Pennsylvania, 2025.
[5] Ayala, M. M.; Blaj, C.; Menard, M.; et al. Combination of RAS (ON) mutant-selective and multi-selective inhibitors sensitizes immune-refractory, RAS-driven preclinical models to immunotherapy.2025, 85 (8_Supplement_1), 6046-6046.
