Chemical 'Jekyll and Hyde's: small-molecule inhibitors of developmental signaling pathways - PubMed (original) (raw)

Review

. 2011 Aug;40(8):4318-31.

doi: 10.1039/c1cs15019g. Epub 2011 Apr 19.

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Review

Chemical 'Jekyll and Hyde's: small-molecule inhibitors of developmental signaling pathways

Tomoyo Sakata et al. Chem Soc Rev. 2011 Aug.

Abstract

Small molecules that perturb developmental signaling pathways can have devastating effects on embryonic patterning, as evidenced by the chemically induced onset of cyclopic lambs and children with severely shortened limbs during the 1950s. Recent studies, however, have revealed critical roles for these pathways in human disorders and diseases, spurring the re-examination of these compounds as new targeted therapies. In this tutorial review, we describe four case studies of teratogenic compounds, including inhibitors of the Hedgehog (Hh), Wnt, and bone morphogenetic protein (BMP) pathways. We discuss how these teratogens were discovered, their mechanisms of action, their utility as molecular probes, and their potential as therapeutic agents. We also consider current challenges in the field and possible directions for future research.

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Figures

Figure 1

Figure 1. Pharmacological inhibition of Hh signaling

(A) Cyclopic lamb resulting from in utero exposure to the natural product cyclopamine. Photo courtesy of the USDA-Agricultural Research Service, Poisonous Plant Research Lab, Logan, Utah. (B) Chemical structures of cyclopamine and synthetic derivatives used to identify its cellular target. Individual ring systems within the cyclopamine skeleton are labeled A–F. (C) Schematic representation of the Hh pathway, showing the trafficking of signaling proteins through the microtubule-containing primary cilium and nucleus (dashed box). Key phosphorylation events are indicated by the black circles and the putative Gli activation step is depicted by the red diamond. (D) Chemical structures of selected Smo antagonists currently being evaluated in human clinical trials. (E) Response and relapse of metastatic medulloblastoma (dark signals) to GDC-0449 therapy. Reprinted with permission from the Massachusetts Medical Society (Ref. , copyright 2009).

Figure 2

Figure 2. Pharmacological inhibition of Wnt signaling

(A) Schematic representation of the Wnt pathway, with key phosphorylation events indicated by the black circles and the nucleus depicted by the dashed box. (B) Chemical structures of the Wnt pathway inhibitors IWR-1, IWR-3, and XAV939.

Figure 3

Figure 3. Pharmacological inhibition of BMP signaling

(A) Schematic representation of the BMP pathway, with key phosphorylation events indicated by the black circles and the nucleus depicted by the dashed box. (B) Chemical structures of dorsomorphin and its chemical analogs LDN-193189 and DMH1. (C) Reduction of heterotopic ossification by LDN-193189 in a mouse model of fibrodysplasia ossificans progressiva. X-ray images of mice with ectopic expression of ALK2-Q207D in their left hindlegs are shown, with soft tissue calcification resulting in animals treated with vehicle alone (arrowheads). Adapted by permission from Macmillian Publishers Ltd: Nature Medicine (Ref. , copyright 2008).

Figure 4

Figure 4. Thalidomide and its mechanism of action

(A) Chemical structures of thalidomide and an affinity matrix conjugated to its carboxyl derivative FR259625. (B) Limb deformities caused by in utero exposure to thalidomide. Reprinted with permission from the British Medical Journal Publishing Group, Ltd. (Ref. , copyright 1992). (C) Inhibition of Crbn-dependent ubiquitination of a putative protein that is required limb development and possibly angiogenesis and immune responses. (D) Pectoral defects (arrowheads) in thalidomide-treated zebrafish embryos. Adapted with permission from the American Association for the Advancement of Science (Ref. , copyright 2010). (E) Schematic representation of the Fgf8/Fgf10 feedback loop that promotes limb outgrowth, with the Fgf8-expressing apical epidermal ridge depicted in orange and the underlying Fgf10-expressing mesenchyme depicted in blue.

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