(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: A Wingless β-Catenin Agonist That Increases Bone Formation Rate

Pelletier, Jeffrey C.; Lundquist, Joseph T.; Gilbert, Adam M.; Alon, N.; Bex, Frederick J.; Bhat, Bheem M.; Bursavich, Matthew G.; Coleburn, Valerie E.; Felix, Luciana A.; Green, Daniel M.; Green, Paula; Hauze, Diane B.; Kharode, Yogendra; Lam, Hieu; Lockhead, Susan; Magolda, Ronald L.; Matteo, Jeanne J.; Mehlmann, John F.; Milligan, Colleen; Murrills, Richard J.; Pirrello, Jennifer; Selim, Sally A.; Sharp, Michael; Unwalla, Ray; Vera, Matthew D.; Wrobel, Jay; Yaworsky, Paul J.; Bodine, Peter V.N.

doi:10.1021/jm9014197

Cited by 45 publications

(34 citation statements)

References 18 publications

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“…Hematoxylin and eosin (H&E) and periodic acid-Schiff base (PAS) staining and scoring of lung tissues also showed that Dkk1 d/d mice had reduced inflammation and leukocyte infiltration compared to WT mice ( Figure 1G, 1H and 1I ). We also showed that airway resistance increase by HDM was notably decreased by using the Dkk-1 inhibitor, (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine) (Pelletier et al, 2009) (WAY-262611) or in Dkk1 d/d mice ( Supplementary Figure 1F ). Taken together, our results demonstrate that lack of Dkk-1 protects the host from chronic type 2 cell-mediated immune responses in the HDM-induced asthma model.…”

Section: Resultsmentioning

confidence: 76%

The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

et al. 2016

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Summary Exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. Here we report the pathological role of the Wnt antagonist Dickkopf-1 (Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-1 polarized T cells to T helper 2 (Th2) cells, stimulating a marked simultaneous induction of the transcription factors c-Maf and Gata-3, mediated by the kinases p38 MAPK and SGK-1, resulting in Th2 cell cytokine production. Circulating Dkk-1 was primarily from platelets, and the increase of Dkk-1 resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocytes infiltration to the affected tissue. Functional inhibition of Dkk-1 impaired Th2 cell cytokine production and leukocyte infiltration, protecting mice from house dust mite (HDM)-induced asthma or Leishmania major infection. These results highlight that Dkk-1 from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation.

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Section: Resultsmentioning

confidence: 76%

The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

et al. 2016

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“…To assess the effect of 'loss of function' of Dkk4, we utilized Dkk inhibitors WAY-262611 and IIIC3, which had previously been shown to inhibit Dkk1 or Dkk2 (Li et al, 2012;Pelletier et al, 2009). Either 2 µM WAY-262611 or 10 µM IIIC3 fully inhibited the binding of Dkk4-AP to HEK293 cells expressing Lrp6, as visualized by AP staining (Fig.…”

Section: Expression Of Dkk4 Transgene In Skin Arrests Further Growth mentioning

confidence: 99%

Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

Sima¹,

Piao²,

Chen³

et al. 2016

Development

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Secreted Dickkopf (Dkk) proteins are major Wnt pathway modulators during organ development. Dkk1 has been widely studied and acts as a general Wnt inhibitor. However, the molecular function of other Dkks remains largely unknown. Here, we show that Dkk4 selectively inhibits a subset of Wnts, but is further inactivated by proteolytic cleavage. Meibomian gland (MG) formation is employed as a model where Dkk4 and its Wnt targets are expressed. Skin-specific expression of Dkk4 arrests MG growth at early germ phase, which is similar to that observed in Eda-ablated Tabby mice. Consistent with transient Dkk4 action, intact Dkk4 inhibits MG extension but the cleaved form progressively increases during MG development with a concomitant upswing in Wnt activity. Furthermore, both Dkk4 and its receptor (and Wnt co-receptor) Lrp6 are direct Eda targets during MG induction. In cell and organotypic cultures, Dkk4 inhibition is eliminated by elevation of Lrp6. Also, Lrp6 upregulation restores MG formation in Tabby mice. Thus, the dynamic state of Dkk4 itself and its interaction with Lrp6 modulates Wnt function during MG development, with a novel limitation of Dkk4 action by proteolytic cleavage.

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“…Screens for Wnt pathway antagonists have utilized luciferase-based TCF reporter elements (5,19,39,40), alkaline phosphatase-conjugated antibodies that recognize TCF/␤-catenin complexes (28), and differentiation-dependent promoters as readouts for hit compounds (53). Each of these methods assesses changes in downstream Wnt signaling.…”

Section: Targeting Wnt Signalingmentioning

confidence: 99%

“…There has been a recent increase in the number of published reports of Wnt pathway modulators (5,15,19,28,32,34,37,39,40,51,58). Many of the studies reflect the efforts of pharmaceutical companies in identifying Wnt active compounds using high-throughput screening approaches.…”

Section: Identification Of Small Molecule Wnt Pathway Regulatorsmentioning

confidence: 99%

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Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach

Chen¹,

Chen²,

Barak

2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Chen W, Chen M, Barak LS. Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach. Am J Physiol Gastrointest Liver Physiol 299: G293-G300, 2010. First published May 27, 2010; doi:10.1152/ajpgi.00005.2010.-Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying small molecule inhibitors of Wnt signaling as tool compounds for research or as precursors to new generations of anticancer drugs. Advancements in robotic technology along with reductions in the costs of equipment, chemical libraries, and information handling have made high-throughput drug discovery programs possible in an academic setting. In this minireview we discuss the most plausible protein targets for inhibiting Wnt signaling in colon cancer therapy, list small molecule Wnt inhibitors that have been identified through recent drug discovery efforts, and provide our laboratory's strategy for identifying novel Wnt signaling antagonists using highthroughput screening. In particular, we summarize the results of a screen of over 1,200 drug and druglike compounds we recently completed in which niclosamide was identified as a Wnt pathway antagonist.Wnt; Frizzled; ␤-catenin; receptor; dishevelled; niclosamide; screening; stem cells SYSTEMATIC PROGRAMS OF DRUG DISCOVERY, once confined primarily to the pharmaceutical industry, are now becoming commonplace in university research programs. The transfer of moderate-to large-scale drug screening capabilities to academic laboratories has been facilitated by recent reductions in the cost of automated screening equipment, compound libraries, and information technology. The identification of small molecule regulators of stem cell signaling associated with cancer development is an area that can benefit greatly as a result of academic screening programs. Presently, there are no small molecules approved by the FDA for the targeted therapy of colon cancer despite its prevalence in the adult population. Wnt signaling appears to be one of the important molecular mechanisms underlying colon cancers, and this has spurred a search for small molecule inhibitors of Wnt pathway proteins. In this minireview we will present a high-throughput screening (HTS) strategy for identifying Wnt pathway signaling antagonists for use in colorectal cancer research and the treatment of colon cancers. Colon Cancer and Targeted TherapiesColorectal cancers are the third most common forms of cancer and the third leading cause of cancer deaths in the United States, and their incidence has remained relatively unchanged (25). In 2008 there were an estimated 149,000 new cases of colorectal cancer diagnosed and 49,960 deaths in the US (22). Small molecule drugs for treating noncancerous diseases of the gastrointestinal tract form one of the largest targeted drug therapy markets; in 2003...

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(1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: A Wingless β-Catenin Agonist That Increases Bone Formation Rate

Cited by 45 publications

References 18 publications

The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development

Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach

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