2. Academic Validation
  3. Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis

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

  • J Med Chem. 2019 Oct 24;62(20):9141-9160. doi: 10.1021/acs.jmedchem.9b01025.
Youngsun Han 1,  Sandip Sengupta 2,  Byung Joo Lee 3 4,  Hanna Cho 1,  Jiknyeo Kim 2,  Hwan Geun Choi 2,  Uttam Dash 2,  Jin Hyoung Kim 3,  Nam Doo Kim 5,  Jeong Hun Kim 3,  Taebo Sim 1 2
Affiliations

Affiliations

  • 1 KU-KIST Graduate School of Converging Science and Technology , Korea University , 145 Anam-ro, Seongbuk-gu , Seoul 02841 , Republic of Korea.
  • 2 Chemical Kinomics Research Center , Korea Institute of Science and Technology (KIST) , 5 Hwarangro 14-gil, Seongbuk-gu , Seoul 02792 , Republic of Korea.
  • 3 Fight Against Angiogenesis-Related Blindness Laboratory, Clinical Research Institute , Seoul National University Hospital , 101 Daehak-ro, Jongno-gu , Seoul 110-744 , Republic of Korea.
  • 4 Department of Biomedical Sciences, College of Medicine , Seoul National University , 103 Daehakro, Jongro-gu , Seoul 110-744 , Republic of Korea.
  • 5 NDBio Therapeutics Inc. , 32 Songdogwahak-ro, Yeonsu-gu , Incheon 21984 , Republic of Korea.
PMID: 31513411 DOI: 10.1021/acs.jmedchem.9b01025
Abstract

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/Flt-4, VEGFR2/KDR/Flk-1, 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/Flt-4 and selectivity over VEGFR2/KDR/Flk-1 and FLT3. 17, a potent dual VEGFR3/Flt-4 and VEGFR2/KDR/Flk-1 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.

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