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YLT192, a novel, orally active bioavailable inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy in preclinical models.

Xia Y, Song X, Li D, Ye T, Xu Y, Lin H, Meng N, Li G, Deng S, Zhang S, Liu L, Zhu Y, Zeng J, Lei Q, Pan Y, Wei Y, Zhao Y, Yu L - Sci Rep (2014)

Bottom Line: However, most these clinical anticancer drugs have unexpected side effects.YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro.It also shows good safety profiles in the studies with mice and rats.

View Article: PubMed Central - PubMed

Affiliation: 1] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China [2].

ABSTRACT
Antagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated, and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100 mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate.

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(A) Chemical structure of YLT192. (B) YLT192 is docked into the active site of VEGFR2, showing interactions between YLT92 and VEGFR2 in the 3-dimentional structure. (C) A 2-dimentional interaction map of YLT192 and VEGFR2.
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f1: (A) Chemical structure of YLT192. (B) YLT192 is docked into the active site of VEGFR2, showing interactions between YLT92 and VEGFR2 in the 3-dimentional structure. (C) A 2-dimentional interaction map of YLT192 and VEGFR2.

Mentions: YLT192 was designed and synthesized in the State Key Laboratory of Biotherapy, Sichuan University (Sichuan, China). Its structural formula and synthesis route was shown in Fig. 1A and Supplementary Figure S1, respectively. The kinase inhibitory activity of YLT192 was measured by the use of radiometric assays provided by Kinase Profile Service (Millipore, UK). The effects of YLT192 on kinase activity were detected using the scintillation proximity assay method at an enzymatic level. As shown in Table 1, YLT192 exhibited great inhibitory activity on VEGFR2 with an inhibitory rate of 93% at 1 μM. In addition, the inhibitory activity of YLT192 was examined against platelet-derived growth factor receptor (PDGFR)-related kinases because of their structural similarity to the VEGFR2. YLT192 showed a relatively low inhibitory rate of 0%, 5%, 7%, and 6% against Fms-like tyrosine kinase 3, PDGFRα, PDGFRβ, and cKit at 1 μM, respectively. Moreover, excellent selectivity for VEGFR2 was evident compared with a range of unrelated tyrosine and serine/threonine kinases, including fibroblast growth factor receptor 3, polo-like kinase 1, aurora-A, Axl, MET, protein kinase A, c-RAF etc. These results indicated that YLT192 was a potent VEGFR2 inhibitor.


YLT192, a novel, orally active bioavailable inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy in preclinical models.

Xia Y, Song X, Li D, Ye T, Xu Y, Lin H, Meng N, Li G, Deng S, Zhang S, Liu L, Zhu Y, Zeng J, Lei Q, Pan Y, Wei Y, Zhao Y, Yu L - Sci Rep (2014)

(A) Chemical structure of YLT192. (B) YLT192 is docked into the active site of VEGFR2, showing interactions between YLT92 and VEGFR2 in the 3-dimentional structure. (C) A 2-dimentional interaction map of YLT192 and VEGFR2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129416&req=5

f1: (A) Chemical structure of YLT192. (B) YLT192 is docked into the active site of VEGFR2, showing interactions between YLT92 and VEGFR2 in the 3-dimentional structure. (C) A 2-dimentional interaction map of YLT192 and VEGFR2.
Mentions: YLT192 was designed and synthesized in the State Key Laboratory of Biotherapy, Sichuan University (Sichuan, China). Its structural formula and synthesis route was shown in Fig. 1A and Supplementary Figure S1, respectively. The kinase inhibitory activity of YLT192 was measured by the use of radiometric assays provided by Kinase Profile Service (Millipore, UK). The effects of YLT192 on kinase activity were detected using the scintillation proximity assay method at an enzymatic level. As shown in Table 1, YLT192 exhibited great inhibitory activity on VEGFR2 with an inhibitory rate of 93% at 1 μM. In addition, the inhibitory activity of YLT192 was examined against platelet-derived growth factor receptor (PDGFR)-related kinases because of their structural similarity to the VEGFR2. YLT192 showed a relatively low inhibitory rate of 0%, 5%, 7%, and 6% against Fms-like tyrosine kinase 3, PDGFRα, PDGFRβ, and cKit at 1 μM, respectively. Moreover, excellent selectivity for VEGFR2 was evident compared with a range of unrelated tyrosine and serine/threonine kinases, including fibroblast growth factor receptor 3, polo-like kinase 1, aurora-A, Axl, MET, protein kinase A, c-RAF etc. These results indicated that YLT192 was a potent VEGFR2 inhibitor.

Bottom Line: However, most these clinical anticancer drugs have unexpected side effects.YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro.It also shows good safety profiles in the studies with mice and rats.

View Article: PubMed Central - PubMed

Affiliation: 1] State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China [2].

ABSTRACT
Antagonizing vascular endothelial growth factor receptor 2 (VEGFR2) to block angiogenesis has been applied toward cancer therapy for its role in promoting cancer growth and metastasis. However, most these clinical anticancer drugs have unexpected side effects. Development of novel VEGFR2 inhibitors with less toxicity remains an urgent need. In this study, we describe a novel, well-tolerated, and orally active VEGFR2 inhibitor, YLT192, which inhibits tumor angiogenesis and growth. YLT192 significantly inhibited kinase activity of VEGFR2 and suppressed proliferation, migration, invasion, and tube formation of human umbilical vascular endothelial cells (HUVEC) in vitro. In addition, it inhibited VEGF-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVEC. Zebrafish embryonic models and alginate-encapsulated tumor cell assays indicated YLT192 also inhibited angiogenesis in vivo. Moreover, YLT192 could directly inhibit proliferation and induce apoptosis of cancer cells in vitro and in vivo. Oral administration of YLT192 at a dose of 100 mg/kg/day could markedly inhibited human tumor xenograft growth without causing obvious toxicities. It decreased microvessel densities (MVD) in tumor sections. It also shows good safety profiles in the studies with mice and rats. Taken together, these preclinical evaluations suggest that YLT192 inhibits angiogenesis and may be a promising anticancer drug candidate.

Show MeSH
Related in: MedlinePlus