ICG 001

ICG001 is a small molecule inhibitor that targets Wnt/β-catenin pathway. It inhibits TCF/β-catenin mediated transcription by competing with β-catenin for CBP (CREB binding protein) but not p300 binding with an IC50 of 3 µM [1]. It can be used to specifically evaluate the role of CBP/beta-catenin association on WNT signaling and cell physiology.

ICG001 have been shown to selectively inhibit colon carcinoma cell lines (SW480 and HCT-116 cells) but not normal colonic epithelial cells (CCD-841Co). It is also efficacious in the Min mouse and nude mouse xenograft models of colon cancer [1]. ICG-001 is a potent inhibitor of GBM stem cells in culture. ICG001 selectively inhibits Wnt/beta-catenin/CREB binding protein (CBP) signaling to reverses pulmonary fibrosis and ameliorate experimental dermal fibrosis in experimental models [2,3]. ICG001 is currently in clinical trial for colon cancer and leukemias.

References:
[1]Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Kim HY, Moon SH, Ha JR, Kahn M. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12682-7.
[2]Henderson WR Jr1, Chi EY, Ye X, Nguyen C, Tien YT, Zhou B, Borok Z, Knight DA, Kahn M. Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14309-14.
[3]Beyer C, Reichert H, Akan H, Mallano T, Schramm A, Dees C, Palumbo-Zerr K, Lin NY, Distler A, Gelse K, Varga J, Distler O, Schett G, Distler JH. Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis. Ann Rheum Dis. 2013 Jul;72(7):1255-8.

The CREB-binding protein inhibitor ICG-001 suppresses pancreatic cancer growth.[Pubmed:25082960]

Mol Cancer Ther. 2014 Oct;13(10):2303-14.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer due in part to a lack of highly robust cytotoxic or molecular-based therapies. Recent studies investigating ligand-mediated Wnt/beta-catenin signaling have highlighted its importance in pancreatic cancer initiation and progression, as well as its potential as a therapeutic target in PDAC. The small-molecule ICG-001 binds cAMP-responsive element binding (CREB)-binding protein (CBP) to disrupt its interaction with beta-catenin and inhibit CBP function as a coactivator of Wnt/beta-catenin-mediated transcription. Given its ability to inhibit Wnt/beta-catenin-mediated transcription in vitro and in vivo, as well as its efficacy in preclinical models of colorectal cancer and other Wnt-driven diseases, we examined ICG-001 and its potential role as a therapeutic in PDAC. ICG-001 alone significantly inhibited anchorage-dependent and -independent growth of multiple PDAC lines, and augmented in vitro growth inhibition when used in combination with gemcitabine. ICG-001 had only variable modest effects on PDAC apoptosis and instead mediated PDAC growth inhibition primarily through robust induction of G(1) cell-cycle arrest. These effects, however, seemed decoupled from its inhibition of Wnt/beta-catenin-mediated transcription. DNA microarrays performed on PDAC cells in the context of ICG-001 treatment revealed ICG-001 altered the expression of several genes with well-established roles in DNA replication and cell-cycle progression, including direct actions on SKP2 and CDKN1A. ICG-001 also significantly prolonged survival in an in vivo orthotopic xenograft model of PDAC, indicating ICG-001 or derived compounds that disrupt CBP activity are potentially useful small-molecule therapeutics for pancreatic cancer.

Canonical Wnt pathway inhibitor ICG-001 induces cytotoxicity of multiple myeloma cells in Wnt-independent manner.[Pubmed:25635944]

PLoS One. 2015 Jan 30;10(1):e0117693.

Canonical Wnt signaling has been implicated in the regulation of multiple myeloma (MM) growth. Here, we investigated whether the targeting of this pathway with a novel pharmacological inhibitor ICG-001 would result in an anti-tumor effect and improvement of chemosensitivity in MM. As expected, ICG-001 specifically down-regulated beta-catenin/TCF-mediated transcription in MM cells. Treatment with ICG-001 resulted in growth arrest and apoptosis in MM cell lines and primary MM cells. Moreover, ICG-001 enhanced the cytotoxic effects of doxorubicin and melphalan and abrogated chemoresistance of MM cells to these chemotherapeutics induced by bone marrow stroma. The cytotoxic effect of ICG-001 was caspase-dependent and mediated through transcriptional up-regulation of BH3-only pro-apoptotic members of the Bcl-2 family Noxa and Puma but not through inhibition of canonical Wnt signaling. ICG-001 selectively induced apoptosis in primary MM cells but did not affect non-MM cells of the bone marrow microenvironment. Experiments using a xenograft model of MM showed substantial anti-tumor effects of this compound in vivo. Thus, our study demonstrated that the small molecule inhibitor ICG-001 has strong anti-MM effects and could be developed further for therapeutic intervention in this disease.

Wnt/beta-catenin signaling inhibitor ICG-001 enhances pigmentation of cultured melanoma cells.[Pubmed:27567978]

J Dermatol Sci. 2016 Nov;84(2):160-168.

BACKGROUND: Wnt/beta-catenin signaling is important in development and differentiation of melanocytes. OBJECTIVE: The object of this study was to evaluate the effects of several Wnt/beta-catenin signaling inhibitors on pigmentation using melanoma cells. METHODS: Melanoma cells were treated with Wnt/beta-catenin signaling inhibitors, and then melanin content and tyrosinase activity were checked. RESULTS: Although some inhibitors showed slight inhibition of pigmentation, we failed to observe potential inhibitory effect of those chemicals on pigmentation of HM3KO melanoma cells. Rather, one of powerful Wnt/beta-catenin signaling inhibitors, ICG-001, increased the pigmentation of HM3KO melanoma cells. Pigmentation-enhancing effect of ICG-001 was reproducible in other melanoma cell line MNT-1. Consistent with these results. ICG-001 increased the expression of pigmentation-related genes, such as MITF, tyrosinase and TRP1. When ICG-001 was treated, the phosphorylation of CREB was significantly increased. In addition, ICG-001 treatment led to quick increase of intracellular cAMP level, suggesting that ICG-001 activated PKA signaling. The blockage of PKA signaling with pharmaceutical inhibitor H89 inhibited the ICG-001-induced pigmentation significantly. CONCLUSIONS: These results suggest that PKA signaling is pivotal in pigmentation process itself, while the importance of Wnt/beta-catenin signaling should be emphasized in the context of development and differentiation.

Interactions between beta-catenin and transforming growth factor-beta signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP).[Pubmed:22241478]

J Biol Chem. 2012 Mar 2;287(10):7026-38.

Interactions between transforming growth factor-beta (TGF-beta) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated beta-catenin-dependent and transforming growth factor-beta1 (TGF-beta1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the beta-catenin/CBP (but not beta-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-beta1-mediated alpha-smooth muscle actin (alpha-SMA) and collagen induction in AEC. We now demonstrate that TGF-beta1 induces LEF/TCF TOPFLASH reporter activation and nuclear beta-catenin accumulation, while LiCl augments TGF-beta-induced alpha-SMA expression, further confirming co-operation between beta-catenin- and TGF-beta-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of beta-catenin and overexpression of ICAT abrogated effects of TGF-beta1 on alpha-SMA transcription/expression, indicating a requirement for beta-catenin in these Smad3-dependent effects. Following TGF-beta treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and beta-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of alpha-SMA via complex formation among Smad3, beta-catenin, and CBP. ICG-001 inhibited alpha-SMA expression/transcription in response to TGF-beta as well as alpha-SMA promoter occupancy by beta-catenin and CBP, demonstrating a previously unknown requisite TGF-beta1/beta-catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by beta-catenin/Smad3 co-localization and CBP expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-beta.

Targeting Wnt signaling in colon cancer stem cells.[Pubmed:21159886]

Clin Cancer Res. 2011 Feb 15;17(4):647-53.

The identification of cancer stem cell (CSC) populations in virtually all tumor types has widespread clinical consequences. CSCs are suggested to be the only cells within malignancies endowed with tumorigenic capacity and are, therefore, directly implicated in therapy resistance and minimal residual disease. The genetic and molecular mechanisms sustaining CSCs are only currently emerging. For instance, aberrant activation of the Wnt signaling pathway is crucial for many cancer types and especially those of the gastrointestinal tract. Indeed, Wnt signaling activity was shown to designate colon CSCs and is, therefore, an attractive target for new therapeutics. Here, we review some of the latest developments that have been achieved to inhibit the Wnt pathway in the context of colon CSCs. Moreover, we discuss some of the pitfalls that can be anticipated and present new opportunities for therapeutic intervention.

A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected].[Pubmed:15314234]

Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12682-7.

Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of beta-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a beta-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates beta-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reduces in vitro growth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.

ICG-001 antagonizes Wnt/β-catenin/TCF-mediated transcription and specifically binds to CREB-binding protein (CBP) with IC50 of 3 μM, but is not the related transcriptional coactivator p300.

ICG 001,847591-62-2,Natural Products,Wnt/β-catenin, buy ICG 001 , ICG 001 supplier , purchase ICG 001 , ICG 001 cost , ICG 001 manufacturer , order ICG 001 , high purity ICG 001