ASTX-029
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MedKoo CAT#: 463912

CAS#: 2095719-92-7

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.


Chemical Structure

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ASTX-029
CAS# 2095719-92-7

Theoretical Analysis

MedKoo Cat#: 463912
Name: ASTX-029
CAS#: 2095719-92-7
Chemical Formula: C29H31ClFN5O5
Exact Mass: 583.1998
Molecular Weight: 584.0454
Elemental Analysis: C, 59.64; H, 5.35; Cl, 6.07; F, 3.25; N, 11.99; O, 13.70

Price and Availability

Size Price Availability Quantity
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 450.0 Ready to ship
100.0mg USD 750.0 Ready to ship
200.0mg USD 1350.0 Ready to ship
500.0mg USD 2650.0 Ready to ship
1.0g USD 3750.0 Ready to ship
2.0g USD 6250.0 Ready to ship
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Synonym: ASTX-029; ASTX029; ASTX 029;

IUPAC/Chemical 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

InChi Key: BVRGQPJKSKKGIH-PUAOIOHZSA-N

InChi Code: 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

SMILES Code: 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

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: 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.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

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.
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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 57.5 98.46

Preparing Stock Solutions

The following data is based on the product molecular weight 584.0454 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Munck JM, Berdini V, Bevan L, Brothwood JL, Castro J, Courtin A, East C, Ferraldeschi R, Heightman TD, Hindley CJ, Kucia-Tran J, Lyons JF, Martins V, Muench S, Murray CW, Norton D, O'Reilly M, Reader M, Rees DC, Rich SJ, Richardson CJ, Shah AD, Stanczuk L, Thompson NT, Wilsher NE, Woolford AJ, Wallis NG. 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. doi: 10.1158/1535-7163.MCT-20-0909. Epub 2021 Jul 30. PMID: 34330842.
In vitro protocol: 1. Munck JM, Berdini V, Bevan L, Brothwood JL, Castro J, Courtin A, East C, Ferraldeschi R, Heightman TD, Hindley CJ, Kucia-Tran J, Lyons JF, Martins V, Muench S, Murray CW, Norton D, O'Reilly M, Reader M, Rees DC, Rich SJ, Richardson CJ, Shah AD, Stanczuk L, Thompson NT, Wilsher NE, Woolford AJ, Wallis NG. 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. doi: 10.1158/1535-7163.MCT-20-0909. Epub 2021 Jul 30. PMID: 34330842.
In vivo protocol: 1. Munck JM, Berdini V, Bevan L, Brothwood JL, Castro J, Courtin A, East C, Ferraldeschi R, Heightman TD, Hindley CJ, Kucia-Tran J, Lyons JF, Martins V, Muench S, Murray CW, Norton D, O'Reilly M, Reader M, Rees DC, Rich SJ, Richardson CJ, Shah AD, Stanczuk L, Thompson NT, Wilsher NE, Woolford AJ, Wallis NG. 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. doi: 10.1158/1535-7163.MCT-20-0909. Epub 2021 Jul 30. PMID: 34330842.

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1: Heightman TD, Berdini V, Bevan L, Buck IM, Carr MG, Courtin A, Coyle JE, Day JEH, East C, Fazal L, Griffiths-Jones CM, Howard S, Kucia-Tran J, Martins V, Muench S, Munck JM, Norton D, O'Reilly M, Palmer N, Pathuri P, Peakman TM, Reader M, Rees DC, Rich SJ, Shah A, Wallis NG, Walton H, Wilsher NE, Woolford AJ, Cooke M, Cousin D, Onions S, Shannon J, Watts J, Murray CW. Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2. J Med Chem. 2021 Aug 26;64(16):12286-12303. doi: 10.1021/acs.jmedchem.1c00905. Epub 2021 Aug 13. PMID: 34387469.

2: Munck JM, Berdini V, Bevan L, Brothwood JL, Castro J, Courtin A, East C, Ferraldeschi R, Heightman TD, Hindley CJ, Kucia-Tran J, Lyons JF, Martins V, Muench S, Murray CW, Norton D, O'Reilly M, Reader M, Rees DC, Rich SJ, Richardson CJ, Shah AD, Stanczuk L, Thompson NT, Wilsher NE, Woolford AJ, Wallis NG. 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. doi: 10.1158/1535-7163.MCT-20-0909. Epub 2021 Jul 30. PMID: 34330842.

ASTX-029

10.0mg / USD 150.0