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ALW-II-41-27 (Synonyms: Eph receptor tyrosine kinase inhibitor;)

Katalog-Nr.GC11134

Ein Multi-Kinase-Inhibitor

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ALW-II-41-27 Chemische Struktur

Cas No.: 1186206-79-0

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

Non-small cell lung cancer (NSCLC) PC-9/ER, PC-9/ERC15, PC-9/ERC16 cell lines

Preparation Method

Four cell lines with acquired resistance to erlotinib were treated with ALW-II-41-27, NG-25, erlotinib, or DMSO for 72 hours, and cell viability was assessed by the MTT assay.

Reaction Conditions

1 µM;72 h

Applications

1 µM ALW-II-41-27 inhibited the proliferation of Erlotinib-resistant NSCLC cell lines and increased cell apoptosis. ALW-II-41-27 induced apoptosis was accompanied by an increase in caspase-3 and PARP and a decrease in the expression of anti-apoptotic proteins BCL-xL and MCL-1.

Animal experiment [2]:

Animal models

6-week-old athymic nude mice

Preparation Method

HCC827/ER or PC-9/ERC16 cells were injected with Matrigel into the hind flanks of 6-week-old athymic nude mice. Mice were randomized by body weight and tumor volume into treatment groups to receive 15 mg/kg of either erlotinib, ALW-II-41-27, or the vehicle alone twice daily via intraperitoneal injection.

Dosage form

15 mg/kg;14 days; i.p.

Applications

After 14 days of the treatment regimen, ALW-II-41-27 significantly inhibited growth of the erlotinib-resistant tumors.

References:

[1]. Amato KR, Wang S, et,al. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res. 2016 Jan 15;76(2):305-18. doi: 10.1158/0008-5472.CAN-15-0717. Epub 2016 Jan 7. PMID: 26744526; PMCID: PMC4715957.

Background

ALW-II-41-27 ist ein Eph-Familien-Tyrosinkinase-Inhibitor mit einer IC50 von 11 nM, um Eph2 zu hemmen[1].

ALW-II-41-27 (1 μM; 72 h) hemmte die Proliferation von Erlotinib-resistenten NSCLC-Zelllinien und erhöhte die Zellapoptose. Die durch ALW-II-41-27 induzierte Apoptose ging mit einer Erhöhung von Caspase-3 und PARP sowie einer Abnahme der Expression anti-apoptotischer Proteine BCL-xL und MCL-1 einher[3]. ALW-II-41-27 (200, 600 oder 1.000 nM ALW-II-41-27; 24, 48 oder 72 h) hemmte die Proliferation, Migration und Invasion von Gebärmutterhalskrebszellen (CC), indem es den RhoA/ROCK-Weg blockierte[4]. ALW-II-41-27 hemmte pY772-EphA2 und EphA2-Y772A verringerte den Hemmeffekt von ALW-II auf NPC-Zellproliferation[6]. Eine kombinierte Behandlung mit ALW-II plus Cetuximab kehrte primäre und erworbene Resistenz gegenüber Cetuximab um, verursachte eine Hemmung des Zellwachstums, induzierte Apoptose und führte zu einem G1-G2-Arrest im Zellzyklus[7].

ALW-II-41-27 (15 mg/kg; 14 Tage; i.p.) hemmte signifikant das Wachstum von erlotinib-resistenten Tumoren[3]. Die Verabreichung von ALW-II-41-27 (15, 30 mg/kg; zweimal täglich; i.p.) hemmte signifikant das H358-Tumorwachstum bei tumortragenden Mäusen. Histologische Analysen zeigten eine signifikante Zunahme der Apoptose in mit ALW-II-41-27 behandelten Tumoren im Vergleich zu denen, die mit NG-25 oder dem Träger behandelt wurden, ähnlich wie bei der genetischen Ablation von EPHA2[2]. ALW-II-41-27 (12,5, 25, 50 und 100 μg/kg; i.p.) verringerte die gastrointestinale Motilität und die Abdominal Withdrawal Reflex (AWR)-Scores deutlich und reduzierte markant die Spiegel oxidativer Stressmarker [4-Hydroxy-2-nonenal (4-HNE), Protein-Carbonyl und 8-Hydroxy-2-de-Axyguanin (8-OHdG)] sowie proinflammatorischer Zytokine (TNF-alpha, IL6, IL17 und ICAM1) und erhöhte den Spiegel antiinflammatorischer Zytokine (IL10) im Serum und Kolon infizierter Mäuse mit Trichinella spiralis[5].

References:
[1]. Choi Y, Syeda F, et,al. Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4467-70. doi: 10.1016/j.bmcl.2009.05.029. Epub 2009 May 13. PMID: 19553108; PMCID: PMC2730633.
[2]. Amato KR, Wang S, et,al. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest. 2014 May;124(5):2037-49. doi: 10.1172/JCI72522. Epub 2014 Apr 8. PMID: 24713656; PMCID: PMC4001547.
[3]. Amato KR, Wang S, et,al. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res. 2016 Jan 15;76(2):305-18. doi: 10.1158/0008-5472.CAN-15-0717. Epub 2016 Jan 7. PMID: 26744526; PMCID: PMC4715957.
[4]. Li X, Li D, et,al.ALW-II-41-27, an EphA2 inhibitor, inhibits proliferation, migration and invasion of cervical cancer cells via inhibition of the RhoA/ROCK pathway. Oncol Lett. 2022 Apr;23(4):129. doi: 10.3892/ol.2022.13249. Epub 2022 Feb 18. PMID: 35251349; PMCID: PMC8895465.
[5]. Zeng L, Li K, et,al.A Novel EphA2 Inhibitor Exerts Beneficial Effects in PI-IBS in Vivo and in Vitro Models via Nrf2 and NF-κB Signaling Pathways. Front Pharmacol. 2018 Mar 27;9:272. doi: 10.3389/fphar.2018.00272. PMID: 29662452; PMCID: PMC5890185.
[6]. Xiang YP, Xiao T, et,al. Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway. Cell Death Dis. 2020 Aug 27;11(8):709. doi: 10.1038/s41419-020-02831-0. PMID: 32848131; PMCID: PMC7449971.
[7]. Martini G, Cardone C, et,al. EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer. Mol Cancer Ther. 2019 Apr;18(4):845-855. doi: 10.1158/1535-7163.MCT-18-0539. Epub 2019 Mar 1. PMID: 30824612.

Chemical Properties

Cas No. 1186206-79-0 SDF
Überlieferungen Eph receptor tyrosine kinase inhibitor;
Chemical Name N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide
Canonical SMILES CCN1CCN(CC2=C(C(F)(F)F)C=C(NC(C3=CC(NC(C4=CN=CC(C5=CC=CS5)=C4)=O)=C(C=C3)C)=O)C=C2)CC1
Formula C32H32F3N5O2S M.Wt 607.69
Löslichkeit ≥ 102 mg/mL in DMSO, ≥ 60.8 mg/mL in EtOH Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 1.6456 mL 8.2279 mL 16.4558 mL
5 mM 0.3291 mL 1.6456 mL 3.2912 mL
10 mM 0.1646 mL 0.8228 mL 1.6456 mL
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