Successful shape-Based virtual screening: The discovery of a potent inhibitor of the type I TGFβ receptor kinase (TβRI)

Singh, Juswinder; Chuaqui, Claudio; Boriack-Sjodin, P.A.; Lee, Wen‐Cherng; Pontz, Timothy; Corbley, Michael J.; Cheung, Hung Kam; Arduini, Robert M.; Mead, Jonathan N.; Newman, Miki; Papadatos, James L.; Bowes, Scott; Josiah, Serene; Ling, Leona

doi:10.1016/j.bmcl.2003.09.028

Cited by 164 publications

(137 citation statements)

References 13 publications

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“…The compound was found to inhibit the PAI-1 promoter activity induced by TGF-h in a dose-dependent manner with a IC 50 of f40 nmol/L (Fig. 1A), which is similar to the previously reported IC 50 (15,16). It also significantly inhibited the activity of the transcriptional activity of a constitutively active ThRI (data not shown).…”

Section: Resultssupporting

confidence: 89%

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Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor

Bandyopadhyay¹,

Agyin²,

Wang³

et al. 2006

Cancer Research

179

129

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Transforming growth factor-B (TGF-B) signaling has been shown to promote invasion and metastasis in various models of human cancers. In this study, we investigated the efficacy of a TGF-B type I receptor kinase inhibitor (TBRI-I) to limit early systemic metastases in an orthotopic xenograft model of lung metastasis and in an intracardiac injection model of experimental bone and lung metastasis using human breast carcinoma MDA-MB-435-F-L cells, a highly metastatic variant of human breast cancer MDA-MB-435 cells, expressing the enhanced green fluorescent protein (EGFP). Treatment of the cells with the TBRI-I had no effect on their growth but blocked TGF-B-stimulated expression of integrin A v B 3 and cell migration in vitro. Systemic administration of the TBRI-I via i.p. injection effectively reduced the number and size of the lung metastasis in both orthotopic xenograft and experimental metastasis models with no effects on primary tumor growth rate compared with controls. TBRI-I treatment also reduced the incidence of widespread early skeletal metastases in the femur, tibia, mandible, and spine detected by wholebody EGFP fluorescence imaging. Tumor burden in femora and tibiae was also reduced after TBRI-I treatment as detected by histomorphometry analysis compared with the placebo controls. Our results indicate for the first time that abrogation of TGF-B signaling by systemic administration of the TBRI-I can inhibit both early lung and bone metastasis in animal model systems and suggest antimetastatic therapeutic potential of the TBRI-I. (Cancer Res 2006; 66(13): 6714-21)

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Section: Resultssupporting

confidence: 89%

“…The ThRI-I used in the current study was initially described by two reports as a highly efficacious and specific inhibitor of ThRI (15,16). To confirm the TGF-h antagonistic activity of the ThRI-I synthesized by us, several assays were done.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor

Bandyopadhyay¹,

Agyin²,

Wang³

et al. 2006

Cancer Research

179

129

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“…We found that the presence of p53 R175H repressed the anchorage-independent growth ability of PC-3/mp53 cells compared with cells without mp53. Interestingly, the colony formation was more dramatically inhibited by TGF-␤, and the treatment with HTS466284, an RI kinase inhibitor (29), significantly stimulated colony formation in PC-3/mp53 cells (Fig. 2, B and C).…”

Section: Mutant P53 Represses Oncogenic Role Of Tgf-␤ and Enhances Tgmentioning

confidence: 93%

“…Chemicals-The small RI kinase inhibitor HTS466284 reported previously to be an ATP-competitive inhibitor of RI kinase (29) was synthesized by the Chemical Synthesis Core of Vanderbilt University. U0126 is an MEK-1/2 inhibitor from Calbiochem.…”

Section: Methodsmentioning

confidence: 99%

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Lin

Yang

et al. 2011

Journal of Biological Chemistry

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“…This TGFhdriven injury response in human cancers and particularly in PDA may contribute to the invasive and metastatic potential of tumors. Therefore, targeting of the TGFh signaling pathway would be a rational therapeutic approach in PDA (53,54). The treatment of several pancreatic cancer cell lines with intact SMAD4 (Mia PaCa-2 and Panc-1) or absent SMAD4 (BxPC-3, CFPAC-1, CaPan-2, AsPC-1, and Hs766T) with a specific TGFh receptor (TGFhR) I serine/ threonine kinase inhibitor SD-093 had no effect on cell growth or apoptosis but inhibited BxPC-3 cell motility and invasiveness by 50% but without any effect on Panc-1 cell motility.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

Mahadevan

Hoff

2007

Molecular Cancer Therapeutics

540

426

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Successful shape-Based virtual screening: The discovery of a potent inhibitor of the type I TGFβ receptor kinase (TβRI)

Cited by 164 publications

References 13 publications

Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor

Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Tumor-stroma interactions in pancreatic ductal adenocarcinoma

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