DEL-22379
$75.00 – $600.00
DEL-22379 (CAS No.: 181223-80-3), a potent and selective ERK Dimerization inhibitor. DEL-22379 inhibits ERK Dimerization without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. >98% Purity.
Synonyms: DEL22379, ERK Dimerization inhibitor, ERK2 inhibitor
For Research Use Only.
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Description
APIM050410: DEL-22379 is an ERK dimerization Inhibitor. DEL-22379 readily binds to ERK2 with a Kd estimated in the low micromolar range, though binding is detectable even at low nanomolar concentrations. ERK2 dimerization is progressively inhibited with an IC50 of ~0.5 μM.
CAS No.: 181223-80-3
IUPAC/Chemical Name: (E)-N-(3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxoindolin-5-yl)-3-(piperidin-1-yl)propanamide
Molecular Formula: C26H28N4O3
Molecular Weight: 444.55
Purity: >98% Purity
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Note: Please contact us for COA, Spectra, and SDS information.
Background Information:
Constitutive activation of the RAS–ERK pathway occurs in nearly 50% of human cancers. Although several pharmacologic strategies to block this pathway have yielded positive results, long-lasting efficacy has been hampered by acquired resistance mutations that reactivate ERK signaling. As an alternative approach, Herrero and colleagues sought to inhibit ERK dimerization, which specifically regulates the extranuclear function of ERK and has been implicated in tumorigenesis. Screening of small-molecule libraries identified DEL-22379, which successfully blocked ERK dimerization without affecting its phosphorylation; correspondingly, ERK cytoplasmic activity was significantly reduced, whereas its nuclear functions were enhanced. Mutation of residues within the dimerization interface of ERK disrupted the effects of DEL-22379, indicating that the compound binds directly to this interface and blocks dimer formation. DEL-22379 inhibited growth and induced apoptosis in various tumor cell lines harboring mutant BRAF or RAS, whereas wild-type cell lines were resistant. In vivo, DEL-22379 selectively inhibited the growth and metastasis of BRAF-mutant cell line–derived and patient-derived xenografts. Expression of phosphoprotein enriched in astrocytes 15 (PEA15), which retains ERK in the cytoplasm, correlated with levels of ERK dimerization and DEL-22379 sensitivity in BRAF-mutant cells, supporting the idea that the antitumor activity of DEL-22379 is dependent on ERK dimerization. Consistent with this finding, DEL-22379 was ineffective in a RAS-driven melanoma model in zebrafish, in which ERK does not dimerize. Importantly, melanoma cells with NRAS overexpression or MEK1 mutations remained sensitive to DEL-22379 treatment, indicating that the antitumor activity of DEL-22379 is not affected by drug-resistance mechanisms associated with existing inhibitors of the RAS–ERK pathway. [1]
Target: ERK, ERK2
IC50: 0.5 μM
In Vitro: DEL-22379 (CAS No. 181223-80-3) is an ERK dimerization inhibitor. DEL-22379 abolishes EGF-induced co-immunoprecipitation of ectopic ERK2 molecules tagged with hemagglutinin (HA) or FLAG epitopes, with an estimated half-maximal inhibitory concentration (IC50) of ~0.5 μM. DEL-22379 inhibits growth of tumor cells harboring RAS-ERK pathway oncogenes. The biological effects of DEL-22379 are investigated on tumor cells in culture. The cytostatic effects of DEL-22379 are compared to those of the MEK inhibitor PD-0325901 and the ERK kinase inhibitor SCH-772984, as reflected by their half-maximal growth inhibitory concentrations (GI50). Cell lines harboring mutant BRAF are the most sensitive to the three compounds. In comparison, wild-type (WT) cell lines for BRAF and RAS are the most resistant, and RAS mutant cells exhibit a range of sensitivities. In cells showing different oncogenic genotypes, distinct sensitivity to DEL-22379 can not be attributed to variations on its effects on dimerization, because DEL-22379 displays similar dimerization- and cytoplasmic signaling-inhibitory dose responses (IC50 of 150-400 nM) regardless of the genotype. [2]
In Vivo: To test DEL-22379 antitumor effects, some of the aforementioned cell lines are xenografted into nude mice, and tumor growth is monitored after intra-peritoneal administration of DEL-22379 at 15 mg/kg. At such a dose, inhibition of ERK dimerization is evident in liver extracts and in xenografted tumors. DEL-22379 markedly inhibits tumor progression for A375 cells (BRAF mutant). [2]
What is the solubility of DEL-22379 in vitro?
DMSO: > 100 mg/mL
What is the solubility of DEL-22379 in vivo?
DMSO, PEG300, Tween-80, saline
Please add DMSO (10%), PEG300 (40%), Tween-80 (5%), saline (45%) in order, solubility ≥ 2.5 mg/mL.
Reference:
[1]. Herrero, A. et al. “Inhibition of ERK Dimerization Impairs RAS–ERK-Driven Tumorigenesis”, Cancer Discov., 2015, 5, DOI: 10.1158/2159-8290.CD-RW2015-156
[2]. Herrero, A. et al. “Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes”, Cancer Cell, 2015, 28, 170-182
[3]. Yang, Y. et al. “Structure-activity relationship study of DEL-22379: ERK dimerization inhibitors with increased safety”, Mol. Divers. 2021, 25, 1051-1075.
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Additional information
Size | 10 mg, 100 mg, 5 mg, 50 mg |
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