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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.CR

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.

Authors+Show Affiliations

Rigel, Inc., 1180 Veteran's Boulevard, South San Francisco, CA 94112, USA. sholland@rigel.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20145120

Citation

Holland, Sacha J., et al. "R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer." Cancer Research, vol. 70, no. 4, 2010, pp. 1544-54.
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;70(4):1544-54.
Holland, S. J., Pan, A., Franci, C., Hu, Y., Chang, B., Li, W., Duan, M., Torneros, A., Yu, J., Heckrodt, T. J., Zhang, J., Ding, P., Apatira, A., Chua, J., Brandt, R., Pine, P., Goff, D., Singh, R., Payan, D. G., & Hitoshi, Y. (2010). R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Research, 70(4), 1544-54. https://doi.org/10.1158/0008-5472.CAN-09-2997
Holland SJ, 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. PubMed PMID: 20145120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. AU - Holland,Sacha J, AU - Pan,Alison, AU - Franci,Christian, AU - Hu,Yuanming, AU - Chang,Betty, AU - Li,Weiqun, AU - Duan,Matt, AU - Torneros,Allan, AU - Yu,Jiaxin, AU - Heckrodt,Thilo J, AU - Zhang,Jing, AU - Ding,Pingyu, AU - Apatira,Ayodele, AU - Chua,Joanne, AU - Brandt,Ralf, AU - Pine,Polly, AU - Goff,Dane, AU - Singh,Rajinder, AU - Payan,Donald G, AU - Hitoshi,Yasumichi, Y1 - 2010/02/09/ PY - 2010/2/11/entrez PY - 2010/2/11/pubmed PY - 2010/4/8/medline SP - 1544 EP - 54 JF - Cancer research JO - Cancer Res. VL - 70 IS - 4 N2 - 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. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/20145120/R428_a_selective_small_molecule_inhibitor_of_Axl_kinase_blocks_tumor_spread_and_prolongs_survival_in_models_of_metastatic_breast_cancer_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=20145120 DB - PRIME DP - Unbound Medicine ER -