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.