R428

• CAT Number: I000223
• CAS Number: 1037624-75-1
• Molecular Formula: C₃₀H₃₄N₈
• Molecular Weight: 506.64
• Purity: ≥95%
• Target: Axl
• Solubility: DMSO: ≤ 10.25 mg/mL
• Storage: 3 years -20C powder
• IC50: 14 nM
• InChI: InChI=1S/C30H34N8/c31-29-33-30(32-24-13-10-20-11-14-25(15-12-22(20)18-24)37-16-3-4-17-37)36-38(29)27-19-23-8-5-7-21-6-1-2-9-26(21)28(23)35-34-27/h1-2,6,9-10,13,18-19,25H,3-5,7-8,11-12,14-17H2,(H3,31,32,33,36)/t25-/m0/s1
• InChIKey: KXMZDGSRSGHMMK-VWLOTQADSA-N
• SMILES: C1CCN(C1)C2CCC3=C(CC2)C=C(C=C3)NC4=NN(C(=N4)N)C5=NN=C6C(=C5)CCCC7=CC=CC=C76

R428 (CAT: I000223) is a potent and selective inhibitor of the receptor tyrosine kinase AXL. AXL is involved in various cellular processes, including cell survival, proliferation, migration, and invasion. By inhibiting AXL signaling, R428 hinders these processes, ultimately leading to the suppression of tumor growth and metastasis. R428 has shown potential as an anti-cancer agent, particularly in solid tumors where AXL overexpression is associated with poor prognosis and resistance to therapy. Additionally, R428 has demonstrated immunomodulatory effects by enhancing antitumor immune responses. It represents a promising therapeutic candidate for targeted cancer treatment and is being actively investigated in preclinical and clinical studies.

Reference

1:Cancer Res. 2010 Feb 15;70(4):1544-54. doi: 10.1158/0008-5472.CAN-09-2997. Epub 2010 Feb 9. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.Holland SJ,Pan A,Franci C,Hu Y,Chang B,Li W,Duan M,Torneros A,Yu J,Heckrodt TJ,Zhang J,Ding P,Apatira A,Chua J,Brandt R,Pine P,Goff D,Singh R,Payan DG,Hitoshi Y, PMID: 20145120 DOI: 10.1158/0008-5472.CAN-09-2997
Abstract: Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. 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. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors.