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 journalArticle

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, 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
Volume62
Issue number20
DOIs
Publication statusPublished - 2019 Oct 24

Fingerprint

Lymphangiogenesis
Lactones
Acids
Inhibitory Concentration 50
Phosphotransferases
Stereoisomerism
Microfluidics
Blood Vessels
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis. / Han, Youngsun; Sengupta, Sandip; Lee, Byung Joo; Cho, Hanna; Kim, Jiknyeo; Choi, Hwan Geun; Dash, Uttam; Kim, Jin Hyoung; Kim, Nam Doo; Kim, Jeong Hun; Sim, Taebo.

In: Journal of Medicinal Chemistry, Vol. 62, No. 20, 24.10.2019, p. 9141-9160.

Research output: Contribution to journalArticle

Han, Y, Sengupta, S, Lee, BJ, Cho, H, Kim, J, Choi, HG, Dash, U, Kim, JH, Kim, ND, Kim, JH & Sim, T 2019, 'Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis', Journal of Medicinal Chemistry, vol. 62, no. 20, pp. 9141-9160. https://doi.org/10.1021/acs.jmedchem.9b01025
Han, Youngsun ; Sengupta, Sandip ; Lee, Byung Joo ; Cho, Hanna ; Kim, Jiknyeo ; Choi, Hwan Geun ; Dash, Uttam ; Kim, Jin Hyoung ; Kim, Nam Doo ; Kim, Jeong Hun ; Sim, Taebo. / Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 20. pp. 9141-9160.
@article{325c882e42a940c09f85876165739203,
title = "Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis",
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, 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.",
author = "Youngsun Han and Sandip Sengupta and Lee, {Byung Joo} and Hanna Cho and Jiknyeo Kim and Choi, {Hwan Geun} and Uttam Dash and Kim, {Jin Hyoung} and Kim, {Nam Doo} and Kim, {Jeong Hun} and Taebo Sim",
year = "2019",
month = "10",
day = "24",
doi = "10.1021/acs.jmedchem.9b01025",
language = "English",
volume = "62",
pages = "9141--9160",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "20",

}

TY - JOUR

T1 - Identification of a Unique Resorcylic Acid Lactone Derivative That Targets Both Lymphangiogenesis and Angiogenesis

AU - Han, Youngsun

AU - Sengupta, Sandip

AU - Lee, Byung Joo

AU - Cho, Hanna

AU - Kim, Jiknyeo

AU - Choi, Hwan Geun

AU - Dash, Uttam

AU - Kim, Jin Hyoung

AU - Kim, Nam Doo

AU - Kim, Jeong Hun

AU - Sim, Taebo

PY - 2019/10/24

Y1 - 2019/10/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85073194155&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073194155&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.9b01025

DO - 10.1021/acs.jmedchem.9b01025

M3 - Article

C2 - 31513411

AN - SCOPUS:85073194155

VL - 62

SP - 9141

EP - 9160

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 20

ER -