ASTX-029

• CAS: 2095719-92-7
• Catalog Number: ACM2095719927
• Category: Inhibitors
• Molecular Weight: 584.05
• Molecular Formula: C29H31ClFN5O5
• Description: ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor. ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors.
• Synonyms: ASTX-029; ASTX029; ASTX 029
• IUPAC Name: (R)-2-(6-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxoisoindolin-2-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propanamide
• Canonical SMILES: ClC(C(C1=CC=C2C(C(N([C@H](C)C(N[C@H](CO)C3=CC(OC)=CC(F)=C3)=O)C2)=O)=C1)=N4)=CN=C4NC5CCOCC5
• InChI: InChI=1S/C29H31ClFN5O5/c1-16(27(38)34-25(15-37)19-9-20(31)12-22(10-19)40-2)36-14-18-4-3-17(11-23(18)28(36)39)26-24(30)13-32-29(35-26)33-21-5-7-41-8-6-21/h3-4,9-13,16,21,25,37H,5-8,14-15H2,1-2H3,(H,34,38)(H,32,33,35)/t16-,25-/m1/s1
• InChI Key: BVRGQPJKSKKGIH-PUAOIOHZSA-N
• Solubility: Soluble in DMSO
• Appearance: Solid powder
• Shelf Life: >2 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• Biological Target: ASTX-029 is an inhibitor of the extracellular signal-regulated kinases (ERK) 1 and 2, with potential antineoplastic activity that inhibits ERK-dependent tumor cell proliferation and survival.
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 59.64; H, 5.35; Cl, 6.07; F, 3.25; N, 11.99; O, 13.70
• Exact Mass: 583.1998
• HS Tariff Code: 2934.99.9001
• In Vitro Activity: The dual mechanism of ASTX029 was investigated further in cell lines with activating mutations in the MAPK pathway. Following a 2-hour treatment, ASTX029 inhibited the phosphorylation of RSK in a dose-dependent manner in both A375 (BRAFV600E-mutant melanoma) and HCT116 (KRASG13D-mutant colorectal) cells with IC50 values of 3.3 and 4 nmol/L, respectively. In agreement with the observations in cell-free assays, 2-hour treatment of A375 and HCT116 cells with ASTX029 resulted in a decrease in pERK levels with a maximum inhibition of 93% and 94% relative to control levels, respectively. ASTX029 treatment resulted in a dose-dependent cell-cycle arrest in the G1-phase. An increase in the fraction of cells in the sub-G1-phase along with an increase in apoptotic markers such as cleaved PARP and Bim suggested compound treatment induced apoptosis.; Reference: Mol Cancer Ther. 2021 Oct;20(10):1757-1768. https://pubmed.ncbi.nlm.nih.gov/34330842/
• In Vivo Activity: Following a single oral dose of 75 mg/kg ASTX029 to mice bearing Colo205 (BRAFV600E-mutant colorectal) tumor xenografts, maximal plasma, and tumor exposure was reached within 0.5 hours and was detectable up to 24 hours. In addition to inhibiting ERK catalytic activity, ASTX029 treatment also resulted in a decrease in tumor pERK levels. This was maximal at 1-hour post-dose, with pERK levels reduced to 35% of control. Levels then increased with time and were fully restored to untreated levels by 24 hours. Following ASTX029 treatment an increase in Bim, cleaved caspase 3 and cleaved PARP was observed, suggesting induction of apoptosis in the tumors. Once daily oral administration of ASTX029 to Colo205 (BRAFV600E-mutant colorectal cancer) tumor-bearing mice significantly inhibited tumor growth in a dose-dependent manner over the range of 25 to 75 mg/kg, with tumor regressions observed at 75 mg/kg. Administering ASTX029 at 150 mg/kg every other day also resulted in tumor regression (P < 0.0001).; Reference: Mol Cancer Ther. 2021 Oct;20(10):1757-1768. https://pubmed.ncbi.nlm.nih.gov/34330842/
• Shipping: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).