Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis

Youngsun Han, Sandip Sengupta, Byung Joo Lee, Hanna Cho, Jiknyeo Kim, Hwan Geun Choi, Uttam Dash, Jin Hyoung Kim, Nam Doo Kim, Jeong Hun Kim, Taebo Sim

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


We synthesized 11 novel L-783277 derivatives, in which a structure rigidifying phenyl ring is incorporated into the 14-membered chiral resorcylic acid lactone system. The SAR study with these substances demonstrated that 17 possesses excellent kinase selectivity against a panel of 335 kinases in contrast to L-783277 and inhibits VEGFR3, VEGFR2, and FLT3 with single-digit nanomolar IC50 values. Also, we found that 21, a stereoisomer of 17, has excellent potency (IC50 = 9 nM) against VEGFR3 and selectivity over VEGFR2 and FLT3. 17, a potent dual VEGFR3 and VEGFR2 inhibitor, effectively suppresses both lymphangiogenesis and angiogenesis in a 3D-microfluidic tumor lymphangiogenesis assay and in vivo corneal assay while SAR131675 blocks only lymphangiogenesis. In addition, 17 blocks the endothelial tube formation and suppresses proliferation of PHE tumor vascular model. 17 will be a valuable templatefor developing therapeutically active and selective substances that target both lymphangiogenesis and angiogenesis.

Original languageEnglish
Pages (from-to)9141-9160
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number20
Publication statusPublished - 2019 Oct 24

Bibliographical note

Funding Information:
This work was supported by Korea Institute of Science and Technology (KIST), the KU-KIST Graduate School of Converging Science and Technology Program, Support for Candidate Development Program (NRF-2016M3A9B5940991), the Global Frontier Project Program (NRF-2016M3A6A4953120) and Bio & Medical Technology Development Program (NRF-2015M3A9E6028949) of the National Research Foundation of Korea funded by the Ministry of Science and ICT.

Publisher Copyright:
© 2019 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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