SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models
Background: Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed. Methods: In this investigati...
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Cell Physiol Biochem Press GmbH & Co KG
2013-07-01
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doaj-52e5fe6895a444fea7662bafa09e901b2020-11-24T21:26:05ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782013-07-0132113815310.1159/000350123350123SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma ModelsXin ChenPan JiHui-Wen YangLing-Ling YangShu ZhouLei ZhongShuang MaXiao-Yu FuChan ZhouGuo-Bo LiMing-Wu ZhengYu-Quan WeiSheng-Yong YangBackground: Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed. Methods: In this investigation, we assessed the in vitro and in vivo anti-melanoma activities of SC-535, which is a novel small molecule multikinase inhibitor discovered by us recently. We analyzed inhibitory effects of SC-535 on various melanoma cell lines and human umbilical vascular endothelial cells (HUVEC) in vitro. Tumor xenografts in athymic mice were used to examine the in vivo activity of SC-535. Results: SC-535 could efficiently inhibit vascular endothelial growth factor receptor (VEGFR) 1/2/3, B-RAF, and C-RAF kinases. It showed significant antiangiogenic potencies both in vitro and in vivo and considerable anti-proliferative ability against several melanoma cell lines. Oral administration of SC-535 resulted in dose-dependent suppression of tumor growth in WM2664 and C32 xenograft mouse models. Studies of mechanisms of action indicated that SC-535 suppressed the tumor angiogenesis and induced G2/M phase cell cycle arrest in human melanoma cells. SC-535 possesses favorable pharmacokinetic properties. Conclusion: All of these results support SC-535 as a potential candidate for clinical studies in patients with melanoma.http://www.karger.com/Article/FullText/350123SC-535BRAFCRAFG2/M phase cell cycle arrestAntiangiogenesis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xin Chen Pan Ji Hui-Wen Yang Ling-Ling Yang Shu Zhou Lei Zhong Shuang Ma Xiao-Yu Fu Chan Zhou Guo-Bo Li Ming-Wu Zheng Yu-Quan Wei Sheng-Yong Yang |
spellingShingle |
Xin Chen Pan Ji Hui-Wen Yang Ling-Ling Yang Shu Zhou Lei Zhong Shuang Ma Xiao-Yu Fu Chan Zhou Guo-Bo Li Ming-Wu Zheng Yu-Quan Wei Sheng-Yong Yang SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models Cellular Physiology and Biochemistry SC-535 BRAF CRAF G2/M phase cell cycle arrest Antiangiogenesis |
author_facet |
Xin Chen Pan Ji Hui-Wen Yang Ling-Ling Yang Shu Zhou Lei Zhong Shuang Ma Xiao-Yu Fu Chan Zhou Guo-Bo Li Ming-Wu Zheng Yu-Quan Wei Sheng-Yong Yang |
author_sort |
Xin Chen |
title |
SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models |
title_short |
SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models |
title_full |
SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models |
title_fullStr |
SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models |
title_full_unstemmed |
SC-535, a Novel Oral Multikinase Inhibitor, Showed Potent Antitumor Activity in Human Melanoma Models |
title_sort |
sc-535, a novel oral multikinase inhibitor, showed potent antitumor activity in human melanoma models |
publisher |
Cell Physiol Biochem Press GmbH & Co KG |
series |
Cellular Physiology and Biochemistry |
issn |
1015-8987 1421-9778 |
publishDate |
2013-07-01 |
description |
Background: Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed. Methods: In this investigation, we assessed the in vitro and in vivo anti-melanoma activities of SC-535, which is a novel small molecule multikinase inhibitor discovered by us recently. We analyzed inhibitory effects of SC-535 on various melanoma cell lines and human umbilical vascular endothelial cells (HUVEC) in vitro. Tumor xenografts in athymic mice were used to examine the in vivo activity of SC-535. Results: SC-535 could efficiently inhibit vascular endothelial growth factor receptor (VEGFR) 1/2/3, B-RAF, and C-RAF kinases. It showed significant antiangiogenic potencies both in vitro and in vivo and considerable anti-proliferative ability against several melanoma cell lines. Oral administration of SC-535 resulted in dose-dependent suppression of tumor growth in WM2664 and C32 xenograft mouse models. Studies of mechanisms of action indicated that SC-535 suppressed the tumor angiogenesis and induced G2/M phase cell cycle arrest in human melanoma cells. SC-535 possesses favorable pharmacokinetic properties. Conclusion: All of these results support SC-535 as a potential candidate for clinical studies in patients with melanoma. |
topic |
SC-535 BRAF CRAF G2/M phase cell cycle arrest Antiangiogenesis |
url |
http://www.karger.com/Article/FullText/350123 |
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