A8329-5mg | R428 [1037624-75-1] Clinisciences

R428 is a selective Axl inhibitor with an IC50 of 14 nM, more than 50-fold sensitivity for Axl than Abl, Mer, Tyro3, InsR, EGFR, HER2, and PDGFR.

Axl receptor tyrosine kinase transduces signals from extracellular matrix into cytoplasma by binding to the vitamin K-dependent protein growth arrest-specific 6 (Gas6). It is involved in several cellular processes including growth, migration, aggregation and anti-inflammation.

R428 blocks the catalytic activity of Axl, at low nanomolar concentration. [1] Axl-dependent activities, including Akt phosphorylation, cell invasion, proinflammatory cytokine production are inhibited. R428 administration reduces the expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. It also inhibits angiogenesis, reduces metastatic tumor burden and extends survival in animal xenograft models. In addition, R428 synergizes with cisplatin to enhance suppression of liver micrometastasis.

R428 can be administrated orally.

References:
[1]Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolong survival in models of metastatic breast cancer. Cancer Res 2010. 70(4): 1544-1554.

1. Bryan J González, Haoquan Zhao, et al. "Reduced calcium levels and accumulation of abnormal insulin granules in stem cell models of HNF1A deficiency." Commun Biol. 2022 Aug 2;5(1):779. PMID: 35918471
2. Nil Vanli, Jinghao Sheng, et al. "Ribonuclease 4 is associated with aggressiveness and progression of prostate cancer." Commun Biol. 2022 Jun 25;5(1):625. PMID: 35752711
3. Samuel D. Zwernik, Beau H. Adams, et al. "AXL receptor is required for Zika virus strain MR-766 infection in human glioblastoma cell lines." Mol Ther Oncolytics. 2021 Nov 11;23:447-457. PMID: 34901388
4. Sekyu Choi, Bing Zhang, et al. "Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence." Nature. 2021 Apr;592(7854):428-432. PMID: 33790465
5. Qi Bian, Joshua C. Anderson, et al. "Mesangioproliferative Kidney Diseases and Platelet-Derived Growth Factor–Mediated AXL Phosphorylation." Kidney Medicine.Available online 30 July 2021.
6. Afnan Abu-Thuraia, Marie-Anne Goyette, et al. "AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network." Nat Commun. 2020 Jul 17;11(1):3586. PMID: 32681075
7. McDaniel NK, Iida M, et al. "AXL Mediates Cetuximab and Radiation Resistance Through Tyrosine 821 and the c-ABL Kinase Pathway in Head and Neck Cancer." Clin Cancer Res. 2020;10.1158/1078-0432.CCR-19-3142. PMID: 32439698
8. Tsai KYF, Hirschi Budge KM, et al. "RAGE and AXL expression following secondhand smoke (SHS) exposure in mice." Exp Lung Res. 2019 Nov - Dec;45(9-10):297-309. PMID: 31762322
9. Hirschi KM, Tsai KYF, et al. "Growth Arrest Specific Protein (Gas)-6/AXL Signaling Induces Preeclampsia (PE) in Rats." Biol Reprod. 2019 Jul 26. pii: ioz140. PMID: 31347670
10. Goyette MA, Cusseddu R, et al. "AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer." Oncotarget. 2019 Mar 12;10(21):2055-2067. PMID: 31007848
11. Chen F, Song Q, et al. "Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition." Am J Cancer Res. 2018 Aug 1;8(8):1466-1482. PMID: 30210917
12. McDaniel NK, Cummings CT, et al. "MERTK mediates intrinsic and adaptive resistance to AXL-targeting agents." Mol Cancer Ther. 2018 Aug 9. pii: molcanther.1239.2017. PMID: 30093568
13. Goyette MA, Duhamel S, et al. "The Receptor Tyrosine Kinase AXL Is Required at Multiple Steps of the Metastatic Cascade during HER2-Positive Breast Cancer Progression." Cell Rep. 2018 May 1;23(5):1476-1490. PMID: 29719259
14. Zuo Q, Liu J, et al. "AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma." Oncogene. 2018 Mar 19. PMID: 29551771
15. Sui L, Danzl N, et al. "Beta Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells. Diabetes." 2017 Sep 20. pii: db170120. PMID: 28931519
16. Xi Y, Kim T, et al. "Local lung hypoxia determines epithelial fate decisions during alveolar regeneration." Nat Cell Biol.2017 Aug;19(8):904-914. PMID: 28737769
17. Singh PK, Guest JM, et al. "Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes." JCI Insight. 2017 Feb 23;2(4):e92340. PMID: 28239662
18. Retallack H, Di Lullo E, et al. "Zika virus cell tropism in the developing human brain and inhibition by azithromycin." Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14408-14413. PMID: 27911847
19. Liu S, DeLalio LJ, et al. "AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus." Circ Res. 2016 Nov 11;119(11):1183-1189. PMID: 27650556
20. Tabata T, Petitt M, et al. "Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission. Cell Host Microbe." 2016 Aug 10;20(2):155-66. PMID: 27443522

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Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	506.64
Cas No.	1037624-75-1
Formula	C₃₀H₃₄N₈
Synonyms	R-428; R 428; BGB324; Bemcentinib
Solubility	≥25 mg/mL in DMSO with gentle warming; insoluble in H2O; insoluble in EtOH
Chemical Name	1-(6,7-dihydro-5H-benzo[2,3]cyclohepta[2,4-d]pyridazin-3-yl)-3-N-[(7S)-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1,2,4-triazole-3,5-diamine
SDF	Download SDF
Canonical SMILES	C1CCN(C1)C2CCC3=C(CC2)C=C(C=C3)NC4=NN(C(=N4)N)C5=NN=C6C(=C5)CCCC7=CC=CC=C76
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Cell experiment:[1]
Cell lines	MDA-MB-231 cells, 4T1 cells and Hela cells.
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	Five-point R428 dose titration (≤10 μM); Cells were preincubated with R428 for 3 h.
Applications	R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production.
Animal experiment:[2]
Animal models	Female BALB/c mice were inoculated in the mammary fat pad with 0.5 × 10⁶ 4T1 cells.
Dosage form	Oral dosing with R428 (7-75 mg/kg twice daily) or vehicle continued until days 19 to 21.
Applications	Oral administration of R428 displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P<0.05) mouse models of breast cancer metastasis.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1]. Holland SJ, Pan A, Franci C et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010 Feb 15;70(4):1544-54.