In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. / Hao, Jijun; Ho, Joshua N; Lewis, Jana A; Karim, Kaleh A; Daniels, R Nathan; Gentry, Patrick R; Hopkins, Corey R; Lindsley, Craig W; Hong, Charles C.

In: ACS chemical biology, Vol. 5, No. 2, 19.02.2010, p. 245-53.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Hao, J, Ho, JN, Lewis, JA, Karim, KA, Daniels, RN, Gentry, PR, Hopkins, CR, Lindsley, CW & Hong, CC 2010, 'In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors', ACS chemical biology, vol. 5, no. 2, pp. 245-53. https://doi.org/10.1021/cb9002865

APA

Hao, J., Ho, J. N., Lewis, J. A., Karim, K. A., Daniels, R. N., Gentry, P. R., ... Hong, C. C. (2010). In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS chemical biology, 5(2), 245-53. https://doi.org/10.1021/cb9002865

Vancouver

Hao J, Ho JN, Lewis JA, Karim KA, Daniels RN, Gentry PR et al. In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS chemical biology. 2010 Feb 19;5(2):245-53. https://doi.org/10.1021/cb9002865

Author

Hao, Jijun ; Ho, Joshua N ; Lewis, Jana A ; Karim, Kaleh A ; Daniels, R Nathan ; Gentry, Patrick R ; Hopkins, Corey R ; Lindsley, Craig W ; Hong, Charles C. / In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. In: ACS chemical biology. 2010 ; Vol. 5, No. 2. pp. 245-53.

Bibtex

@article{767e6ce03bfc426b92d2813ed906fb86,
title = "In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors",
abstract = "The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we identified dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has significant {"}off-target{"} effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether dorsomorphin's antiangiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogues that target BMP but not VEGF signaling and vice versa. In a structure-activity relationship (SAR) study of dorsomorphin analogues based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the BMP inhibitors, DMH1, which exclusively targets the BMP but not the VEGF pathway, dorsalized the embryonic axis without disrupting the angiogenic process, demonstrating that BMP signaling was not involved in the angiogenic process. This is one of the first full-scale SAR studies performed in vertebrates and demonstrates the potential of zebrafish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.",
keywords = "Animals, Bone Morphogenetic Proteins/antagonists & inhibitors, Drug Evaluation, Preclinical/methods, Embryo, Nonmammalian/drug effects, Pyrazoles/chemistry, Pyrimidines/chemistry, Quinolines/chemistry, Structure-Activity Relationship, Vascular Endothelial Growth Factor A/antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors, Zebrafish/embryology",
author = "Jijun Hao and Ho, {Joshua N} and Lewis, {Jana A} and Karim, {Kaleh A} and Daniels, {R Nathan} and Gentry, {Patrick R} and Hopkins, {Corey R} and Lindsley, {Craig W} and Hong, {Charles C}",
year = "2010",
month = "2",
day = "19",
doi = "10.1021/cb9002865",
language = "English",
volume = "5",
pages = "245--53",
journal = "A C S Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "2",

}

RIS

TY - JOUR

T1 - In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors

AU - Hao, Jijun

AU - Ho, Joshua N

AU - Lewis, Jana A

AU - Karim, Kaleh A

AU - Daniels, R Nathan

AU - Gentry, Patrick R

AU - Hopkins, Corey R

AU - Lindsley, Craig W

AU - Hong, Charles C

PY - 2010/2/19

Y1 - 2010/2/19

N2 - The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we identified dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has significant "off-target" effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether dorsomorphin's antiangiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogues that target BMP but not VEGF signaling and vice versa. In a structure-activity relationship (SAR) study of dorsomorphin analogues based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the BMP inhibitors, DMH1, which exclusively targets the BMP but not the VEGF pathway, dorsalized the embryonic axis without disrupting the angiogenic process, demonstrating that BMP signaling was not involved in the angiogenic process. This is one of the first full-scale SAR studies performed in vertebrates and demonstrates the potential of zebrafish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.

AB - The therapeutic potential of small molecule signaling inhibitors is often limited by off-target effects. Recently, in a screen for compounds that perturb the zebrafish embryonic dorsoventral axis, we identified dorsomorphin, the first selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has significant "off-target" effects against the VEGF (vascular endothelial growth factor) type-2 receptor (Flk1/KDR) and disrupts zebrafish angiogenesis. Since both BMP and VEGF signals are known to be involved in vascular development, we sought to determine whether dorsomorphin's antiangiogenic effects are due to its impact on the BMP or VEGF signals through the development of analogues that target BMP but not VEGF signaling and vice versa. In a structure-activity relationship (SAR) study of dorsomorphin analogues based primarily on their effects on live zebrafish embryos, we identified highly selective and potent BMP inhibitors as well as selective VEGF inhibitors. One of the BMP inhibitors, DMH1, which exclusively targets the BMP but not the VEGF pathway, dorsalized the embryonic axis without disrupting the angiogenic process, demonstrating that BMP signaling was not involved in the angiogenic process. This is one of the first full-scale SAR studies performed in vertebrates and demonstrates the potential of zebrafish as an attractive complementary platform for drug development that incorporates an assessment of in vivo bioactivity and selectivity in the context of a living organism.

KW - Animals

KW - Bone Morphogenetic Proteins/antagonists & inhibitors

KW - Drug Evaluation, Preclinical/methods

KW - Embryo, Nonmammalian/drug effects

KW - Pyrazoles/chemistry

KW - Pyrimidines/chemistry

KW - Quinolines/chemistry

KW - Structure-Activity Relationship

KW - Vascular Endothelial Growth Factor A/antagonists & inhibitors

KW - Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors

KW - Zebrafish/embryology

U2 - 10.1021/cb9002865

DO - 10.1021/cb9002865

M3 - Journal article

C2 - 20020776

VL - 5

SP - 245

EP - 253

JO - A C S Chemical Biology

JF - A C S Chemical Biology

SN - 1554-8929

IS - 2

ER -

ID: 213627140