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 -