A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity.
BACKGROUND
Retinoids regulate key developmental pathways throughout life, and have potential uses for differentiation therapy. It should be possible to identify novel retinoids by coupling new chemical reactions with screens using the zebrafish embryonic model.


RESULTS
We synthesized novel retinoid analogues and derivatives by amide coupling, obtaining 80-92% yields. A small library of these compounds was screened for bioactivity in living zebrafish embryos. We found that several structurally related compounds significantly affect development. Distinct phenotypes are generated depending on time of exposure, and we characterize one compound (BT10) that produces specific cardiovascular defects when added 1 day post fertilization. When compared to retinoic acid (ATRA), BT10 shows similar but not identical changes in the expression pattern of embryonic genes that are known targets of the retinoid pathway. Reporter assays determined that BT10 interacts with all three RAR receptor sub-types, but has no activity for RXR receptors, at all concentrations tested.


CONCLUSIONS
Our screen has identified a novel retinoid with specificity for retinoid receptors. This lead compound may be useful for manipulating components of retinoid signaling networks, and may be further derivatized for enhanced activity.
Das
Bhaskar C
BC
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, USA. bhaskar.das@einstein.yu.edu
McCartin
Kellie
K
Liu
Ting-Chun
TC
Peterson
Randall T
RT
Evans
Todd
T
D000818:Animals; D000970:Antineoplastic Agents; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004625:Embryo, Nonmammalian; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries; D014212:Tretinoin / Q000031:analogs & derivatives*; D015027:Zebrafish
D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D054852:Small Molecule Libraries; D014212:Tretinoin