| SP F-021 |
| Modulation of angiogenesis and lymphangiogenesis using SanUDKJN06052, a novel selective triple kinase inhibitor against VEGFR2, VEGFR3 and flt3 |
| 1. Department of Biomedical Sciences, College of Medicine, Seoul National University
2. KU-KIST Graduate School of Converging Science and Technology, Korea University
3. Mechanical Engineering, Seoul National University
4. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST)
5. Department of Ophthalmology, Seoul National University College of Medicine |
| Byungjoo Lee(1), Hanna Cho (2), Youngsun Han(2), Minhwan Chung (3), Teabo Sim (2,4), JeongHun Kim (1,5) |
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목적 : Angiogenesis and lymphangiogenesis are involved in diverse ocular pathologic conditions. Small molecule drugs has several advantages over biosimilars in terms of storage and cost issues. However, diverse off-target effects of small molecule drugs brings about safety concerns. In this study, we have developed a novel selective triple kinase inhibitor against VEGFR2, VEGFR3 and flt3 and validated its efficacy in modulating angiogenesis and lymphangiogenesis.
방법 : Through kinase selectivity profiling system, we screened the inhibitory potential of SanUDKJN06052 against 370 kinases. The efficacy of SanUDKJN06052 for suppressing VEGF165 induced phosphorylation of VEGFR2 was determined. We have tested the inhibitory potential of SanUDKJN06052 for flt3, flt4 and their downstream pathways using mutated Ba/F3 cell in which flt3 or flt4 are constitutively activated. Anti-angiogenic/anti-lymphangiogenic property of SanUDKJN06052 were determined both in vitro (migration and tube formation) and in vivo (mouse model of suture induced corneal lymphangiogenesis).
결과 : SanUDKJN06052 strongly suppressed the kinase activity of VEGFR2 (82%), VEGFR3 (97%), and flt-3 (95%). This compound prevented HUVEC from VEGF165 induced phosphorylation of VEGFR2. In Ba/F3 harboring FLT3 or FLT4 mutant, UDKJN06052 effectively abolished the activation of flt3 or flt4 downstream pathway. SanUDKJN06052 showed a significant inhibitory efficacy in vitro angiogenesis and lymphangiogenesis assay. Topical administration of SanUDKJN06052 effectively decreased the extent of angiogenesis and lymphagiogenesis in suture induced corneal angiogenesis/lymphangiogenesis model.
결론 : We have developed a potent receptor tyrosine kinase inhibitor highly selective to VEGFR2, VEGFR3 and flt3. SanUDKJN06052 can be used as a dual inhibitor of ocular angiogenesis and lymphangiogenesis.
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