ASTX029 (ERK1/2 inhibitor 2) is a highly effective and selective orally bioavailable extracellular signal-regulated kinase (ERK) 1/2 inhibitor (with an IC50 of 2.7nM for ERK2) [1]. ERK1/2 is the terminal kinase in the MAPK pathway, and the activation of the ERK/MAPK pathway is very common in myeloid malignancies [2]. ASTX029 has anti-tumor activity and can be used for cancer treatment [3].
In vivo, ASTX029 (10 and 100nM; 0-72h) can induce cell cycle arrest at the G1 phase in A375 and HCT116 cells and induce apoptosis [4]. ASTX029 (0.1-5nM; 12h) significantly reduced the p-ERK level in primary microglial cells stimulated by lipopolysaccharide (LPS) and inhibited the secretion of IL-1β, IL-6 and TNF-α [5].
In vivo, ASTX029 (50μM; 1μl; intravitreal injection) significantly reduced the p-ERK level in the retina of laser-induced choroidal neovascularization (CNV) mice and reduced the lesion area of CNV [5]. ASTX029 (20-75mg/kg/day; oral) can significantly inhibit tumor growth in Colo205 (BRAFV600E-mutant colorectal cancer) tumor-bearing mice [4].
References:
[1] Munck, J., Berdini, V., Courtin, A., et al. The clinical candidate, ASTX029, is a novel, dual mechanism ERK1/2 inhibitor and has potent activity in MAPK-activated cancer cell lines and in vivo tumor models. Eur. J. Cancer 138(Suppl 2), S53 (2020)
[2] Sharma P, Piya S, Baran N, et al. P460: ERK1/2 inhibition overcomes ressitance to BCL2 inhibition in acute myeloid leukemia by impact on mitochondrial dynamics and function[J]. HemaSphere, 2023, 7(Suppl): e08176db.
[3] Hindley C J, Fazal L, Munck J M, et al. Anti-tumor activity of ASTX029, a dual mechanism inhibitor of ERK1/2, in preclinical AML models[J]. Blood, 2020, 136: 7-8.
[4] Munck JM, et al. ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK. Mol Cancer Ther. 2021 Oct;20(10):1757-1768.
[5] Zou Y, Jiang J, Li Y, et al. Immune Checkpoint PD‐L1 Modulates Retinal Microglial Activation to Alleviate Vascular Leakage in Choroidal Neovascularization via ERK[J]. Advanced Science, 2025: 2400747.
ASTX029 (ERK1/2 inhibitor 2)是一种高效且选择性的具有口服生物利用活性的细胞外信号调节激酶（ERK）1/2抑制剂（对于ERK2的IC50为2.7nM）[1]。ERK1/2是MAPK通路中的末端激酶，ERK/MAPK通路的激活在髓系恶性肿瘤中很常见 [2]。ASTX029具有抗肿瘤活性，可用于癌症的治疗 [3]。
在体外，ASTX029（10和100nM; 0-72h）能够诱导A375和HCT116细胞的细胞周期停滞在G1期，并诱导凋亡 [4]。ASTX029（0.1-5nM; 12h）显著降低了脂多糖（LPS）刺激的原代小胶质细胞中的p-ERK水平，并抑制了IL-1β，IL-6和TNF-α的分泌 [5]。
在体内，ASTX029（50μM; 1μl;玻璃体内注射）显著降低了激光诱导的脉络膜新生血管（CNV）小鼠的视网膜p-ERK水平并减少了CNV病变面积 [5]。ASTX029（20-75mg/kg/day; oral）能够显著抑制Colo205（BRAFV600E-突变型结直肠癌）荷瘤小鼠的肿瘤生长 [4]。