6 It was identified inĪ pathway screen using a modified MRTF-dependent serum response element 4, 5 In 2007, we reported the first small molecule inhibitor of the Rho/MRTF/SRF
Rho/MRTF/SRF signaling has alsoīeen linked to melanoma metastasis and to fibrotic pathological mechanisms. 3 This mechanism feedsīack on cell motility control and has been strongly implicated inĬell migration and proliferation. Pro-fibrotic genes regulated by a serum response element (SRE) in In the expression of structural and cytoskeletal genes, as well as 1, 2 The MRTF/SRF complex activates a gene transcription program involved Rho family of GTPases, which regulates actin cytoskeleton and motility. In the prevention of bleomycin-induced dermal fibrosis.įactor (SRF) are transcription factors activated downstream of the A recently developedĪnalog, CCG-257081, which cocrystallizes with pirin, is also effective Gene expression in primary dermal fibroblasts. Validated pirin inhibitor, we show a role for pirin in TGF-β-induced
Finally, using both siRNA and a previously We also show with genetic approaches that pirin modulates MRTF-dependent We verify that pirin binds these compounds in vitro. Including isothermal titration calorimetry and X-ray crystallography,
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Which yielded pirin, an iron-dependent cotranscription factor, asĪ target of this series of compounds. Here, we describe affinity isolation-based target identification efforts Although these compoundsĪre efficacious in these disease models, the molecular target is unknown. Metastasis and bleomycin-induced fibrosis. Vivo models, including significant reduction of melanoma Through an MRTF/SRF-dependent luciferase screen has shown remarkable Of compounds (including CCG-1423 and CCG-203971) discovered A recently developed analog, CCG-257081, which co crystallizes with pirin, is also effective in the prevention of bleomycin-induced dermal fibrosis. Finally, using both siRNA and a previously validated pirin inhibitor, we show a role for pirin in TGF-β- induced gene expression in primary dermal fibroblasts. We also show with genetic approaches that pirin modulates MRTF- dependent luciferase reporter activity. Using biophysical techniques including isothermal titration calorimetry and X-ray crystallography, we verify that pirin binds these compounds in vitro. Here, we describe affinity isolation-based target identification efforts which yielded pirin, an iron-dependent cotranscription factor, as a target of this series of compounds. Although these compounds are efficacious in these disease models, the molecular target is unknown. A series of compounds (including CCG-1423 and CCG-203971) discovered through an MRTF/SRF-dependent luciferase screen has shown remarkable efficacy in a variety of in vitro and in vivo models, including significant reduction of melanoma metastasis and bleomycin- induced fibrosis.
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