ASTX295 is an orally active and selective MDM2 antagonist with an IC50 of <1 nM. ASTX295 inhibits the MDM2-p53 interaction, activates wild-type TP53, and thereby induces the expression of relevant transcriptional targets, leading to cell death. ASTX295 drives the transition of pancreatic cancer cells from senescence to apoptosis and regulates p53 and DNA damage biomarkers. ASTX295 can be used for the research of hematologic malignancies and pancreatic cancer [1] [2].
In Vivo, ASTX295 (80 mg/kg; p.o.; twice weekly; 6 doses) and PC14586 significantly reduces tumor volume in male CB17 SCID mice bearing BxPC3 xenografts[2]. ASTX295 (80 mg/kg; p.o.; single dose) with PC14586 in BxPC3 tumor-bearing mice significantly increases the levels of p53 signaling pathway biomarkers (tissue p21, plasma GDF-15, p21/MDM2/GDF-15 mRNA in tumor tissue, and multiple protein biomarkers)[2].
In Vitro, ASTX295 (0-10000 nM; up to 72 h) reduces viability in all tested TP53WT lymphoid malignancy cell lines (DLBCL, MCL, T-cell lymphoma) with IC50 values of <1 nM to 100 nM over up to 72 h, induces p53 and p21 expression, and causes maximal cell death at 72 h (24 h in Z138 cells)[1]. ASTX295 (1 μM; 0-24 h, in combination with a p53 corrector) induces sustained upregulation of p53 signaling and DNA damage-related protein and mRNA biomarkers over a 24-hour period in BxPC3 (TP53: Y220C) cells[2].
References:
[1]. Iqbal N, et al. ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies[J]. Blood, 2024, 144: 3591.
[2]. Ward G, et al. Switching cell fate from senescence to apoptosis by the combination of a p53 corrector with the MDM2 antagonist ASTX295[C]//Cancer Research. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2025, 85(8).
In Vivo, ASTX295 (80 mg/kg; p.o.; twice weekly; 6 doses) and PC14586 significantly reduces tumor volume in male CB17 SCID mice bearing BxPC3 xenografts[2]. ASTX295 (80 mg/kg; p.o.; single dose) with PC14586 in BxPC3 tumor-bearing mice significantly increases the levels of p53 signaling pathway biomarkers (tissue p21, plasma GDF-15, p21/MDM2/GDF-15 mRNA in tumor tissue, and multiple protein biomarkers)[2].
In Vitro, ASTX295 (0-10000 nM; up to 72 h) reduces viability in all tested TP53WT lymphoid malignancy cell lines (DLBCL, MCL, T-cell lymphoma) with IC50 values of <1 nM to 100 nM over up to 72 h, induces p53 and p21 expression, and causes maximal cell death at 72 h (24 h in Z138 cells)[1]. ASTX295 (1 μM; 0-24 h, in combination with a p53 corrector) induces sustained upregulation of p53 signaling and DNA damage-related protein and mRNA biomarkers over a 24-hour period in BxPC3 (TP53: Y220C) cells[2].
References:
[1]. Iqbal N, et al. ASTX295 a Novel Potent MDM2 Antagonist Induces More Than One Mechanism of Programmed Cell Death (PCD) in Lymphoid Malignancies[J]. Blood, 2024, 144: 3591.
[2]. Ward G, et al. Switching cell fate from senescence to apoptosis by the combination of a p53 corrector with the MDM2 antagonist ASTX295[C]//Cancer Research. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH, 2025, 85(8).