jijun_cb - In Vivo Structure Activity Relationship Study of...

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In Vivo Structure 2 Activity Relationship Study of Dorsomorphin Analogues IdentiFes Selective VEG± and BMP Inhibitors Jijun Hao , Joshua N. Ho , Jana A. Lewis , Kaleh A. Karim , R. Nathan Daniels § , Patrick R. Gentry ‡, i , Corey R. Hopkins i , Craig W. Lindsley ‡,§, i , ' , and Charles C. Hong †,‡, ' ,#, * Division of Cardiovascular Medicine, Department of Medicine, Department of Pharmacology, § Department of Chemistry, i Vanderbilt Program in Drug Discovery, ' Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and # Research Medicine, Veterans Administration TVHS, Nashville, Tennessee 37212 W ith advances in high-throughput screening capabilities, it is not difFcult to identify com- pounds that target a particular protein or pathway. Rather, a greater challenge lies in identifying selective modulators and improving pharmaceutical, or ADMET (absorption, distribution, metabolism, excretion, and toxicity), properties of lead compounds ( 1 ). In the traditional approach to pharmaceutical development, the initial efforts at lead optimization are focused on identifying structural analogues with the highest po- tency against a therapeutic target in in vitro assays. However, when the subsequent in vivo results clash with the predictions based on tests, it is difF- cult to determine whether such “failures” result from flawed biological underpinnings or compounds’ intrin- sic deFciencies, such as poor target selectivity or subop- timal bioavailability. In principal, these pitfalls can be circumvented with the use of the zebraFsh model early in the lead optimization phase. Rapid external development, trans- parency, and high fecundity make zebraFsh ideal for large-scale characterization of bioactive small molecules ( 2−5 ). Since embryonic cells are capable of integrating multiple signaling pathways to trigger pre- cise developmental outputs, a small molecule that se- lectively targets a signaling pathway involved in embry- onic patterning will phenocopy genetic mutations in that pathway, whereas nonspeciFc compounds will cause early embryonic lethality or nonspeciFc developmental delay. In addition, since drug exposure in embryos oc- curs by passive diffusion, the assessment takes into account compounds’ intrinsic physiochemical prop- *Corresponding author, [email protected] Received for review November 12, 2009 and accepted December 19, 2009. 10.1021/cb9002865 CCC: $ © XXXX American Chemical Society ABSTRACT The therapeutic potential of small molecule signaling inhibitors is of- ten limited by off-target effects. Recently, in a screen for compounds that perturb the zebraFsh embryonic dorsoventral axis, we identiFed dorsomorphin, the Frst selective inhibitor of bone morphogenetic protein (BMP) signaling. Here we show that dorsomorphin has signiFcant “off-target” effects against the VEG± (vascular endothelial growth factor) type-2 receptor (±lk1/KDR) and disrupts zebraFsh angio- genesis. Since both BMP and VEG± signals are known to be involved in vascular de-
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This note was uploaded on 02/17/2011 for the course CHEMISTRY 101 taught by Professor Csr during the Spring '11 term at University of Louisville.

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jijun_cb - In Vivo Structure Activity Relationship Study of...

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