ARS-1620

ARS-1620 is a highly selective, orally active inhibitor of the KRAS p.G12C mutant protein^[1-2]. ARS-1620 irreversibly and covalently binds to the GDP-bound form of the KRAS G12C protein at the Switch-II pocket, locking KRAS in an inactive state and thereby blocking downstream signaling transduction. ARS-1620 is applicable to the study of non-small cell lung cancer, colorectal cancer, pancreatic cancer, and other solid tumors harboring the KRAS p.G12C mutation^[3-4].

In vitro, ARS-1620 (1µM) was used to treat three non-small cell lung cancer cell lines with the KRAS G12C mutation and varying drug sensitivities (H358, Calu1, H1792) for 6 and 24 hours. ARS-1620 significantly inhibited the activity of the MAPK and AKT signaling pathways and activated the ERBB2/3 signaling pathway ^[5]. ARS-1620 (0-1µM) was also applied to three KRAS G12C-mutant lung cancer cell lines (H23, HOP-62, Calu-1) for 14 days. ARS-1620 significantly inhibited colony formation and cell proliferation, and induced a marked upregulation of mTOR gene mRNA expression^[6].

In vivo, ARS-1620 (50-400mg/kg; oral gavage; once daily) was administered for 2 to 3 weeks to mice bearing subcutaneous xenograft tumors derived from human non-small cell lung cancer cells (MIA-PaCa2, H358, H2030, H1373, HCC44, LU99A) with the KRAS p.G12C mutation, as well as to mice with patient-derived xenograft (PDX) models harboring the KRAS p.G12C mutation. ARS-1620 significantly inhibited tumor growth and promoted tumor regression^[7]. In PDX model mice with the KRAS p.G12C mutation, ARS-1620 (100-200mg/kg; oral gavage; 5 times per week for 3 weeks) induced significant tumor growth inhibition and regression, accompanied by a high degree of KRAS G12C target occupancy and inhibition of downstream signaling pathways (RAS-GTP, p-ERK, p-S6)^[8].

References:
[1] Li L, Zhao H, Peng X, et al. Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents. Bioorg Med Chem. 2022 Oct 1;71:116962.
[2] Lin X, Ma Q, Chen L, et al. Identifying genes associated with resistance to KRAS G12C inhibitors via machine learning methods. Biochim Biophys Acta Gen Subj. 2023 Dec;1867(12):130484.
[3] Hansen R, Peters U, Babbar A, et al. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. Nat Struct Mol Biol. 2018 Jun;25(6):454-462.
[4] Shankar S, Tien JC, Siebenaler RF, et al. An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development. Nat Commun. 2020 Jun 4;11(1):2817.
[5] Solanki HS, Welsh EA, Fang B, et al. Cell Type-specific Adaptive Signaling Responses to KRASG12C Inhibition. Clin Cancer Res. 2021 May 1;27(9):2533-2548.
[6] Ito M, Miyata Y, Hirano S, et al. Dual inhibition of GTP-bound KRAS and mTOR in lung adenocarcinoma and squamous cell carcinoma harboring KRAS G12C. Cell Commun Signal. 2025 May 11;23(1):220.
[7] Janes MR, Zhang J, Li LS, et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell. 2018 Jan 25;172(3):578-589.e17.
[8] Molina-Arcas M, Moore C, Rana S, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999.

ARS-1620是一种高选择性的、具有口服活性的KRAS p.G12C突变蛋白抑制剂^[1-2]。ARS-1620通过与KRAS G12C突变蛋白的GDP结合形式（Switch-II pocket）形成不可逆的共价结合，将KRAS锁定在非活性状态，从而阻断其下游信号传导。ARS-1620可用于KRAS p.G12C突变的非小细胞肺癌、结直肠癌、胰腺癌及其他实体瘤的相关研究^[3-4]。

在体外，ARS-1620（1μM）处理三种具有KRAS G12C突变且对药物敏感性不同的非小细胞肺癌细胞系（H358，Calu1，H1792）6小时与24小时后，ARS-1620显著抑制了MAPK和AKT信号通路活性，激活了ERBB2/3信号通路^[5]。ARS-1620（0-1μM）孵育三种携带KRAS G12C突变的肺癌细胞系（H23，HOP-62，Calu-1）14天，ARS-1620显著抑制了细胞的集落形成能力和增殖能力，诱导了mTOR基因mRNA表达的显著上调^[6]。

在体内，ARS-1620（50-400mg/kg；口服灌胃；每日一次）处理携带KRAS p.G12C突变的人源非小细胞肺癌细胞（MIA-PaCa2、H358、H2030、H1373、HCC44、LU99A）的皮下异种移植瘤小鼠以及携带KRAS p.G12C的患者来源异种移植（PDX）模型小鼠，为期2至3周。ARS-1620显著抑制了肿瘤生长和促进肿瘤消退^[7]。在携带KRAS p.G12C突变的PDX模型小鼠中，ARS-1620（100-200mg/kg；口服灌胃；每周5次持续3周）能诱导显著的肿瘤生长抑制和消退，并伴有高度的KRAS G12C靶点占据率以及下游信号通路（RAS-GTP, p-ERK, p-S6）的抑制^[8]。