SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-β Type I Receptors ALK4, ALK5, and ALK7

Byfield, Stacey DaCosta; Major, Christopher; Laping, Nicholas J.; Roberts, Anita B.

doi:10.1124/mol.65.3.744

Cited by 361 publications

(180 citation statements)

References 34 publications

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“…Treatment with SD-208 increased osteoblast differentiation and bone formation as well as reduced osteoclast formation and bone resorption, resulting in increased trabecular bone volume [71]. These data should be interpreted carefully since all known TβRI/ALK5 kinase inhibitors described to date are also equipotent inhibitors of ALK4 [72][73][74][75], which is utilized by the bone matrix-embedded TGF-β superfamily member, Activin. Activin inhibition within bone has been shown in several contexts to promote bone formation and mass [76,77].…”

Section: Tgf-β In Bone Homeostasismentioning

confidence: 88%

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

Buijs

Stayrook

Guise

2011

Cancer Microenvironment

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Breast cancer is the most prevalent cancer among females worldwide. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ∼70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by bone destruction, bone fractures, pain, and hypercalcemia, causing severe morbidity and hospitalization. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-β as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.

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Section: Tgf-β In Bone Homeostasismentioning

confidence: 88%

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

Buijs

Stayrook

Guise

2011

Cancer Microenvironment

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“…SB-203580 inhibits Smad2 phosphorylation by TGF-β RI in vivo and affects TGF-β-dependent transcriptional activation [199]. SB-505124 inhibits ALK4-, ALK5-, and ALK-7-dependent activation of Smad2 and Smad3 and of TGF-β-induced MAP kinase pathway components in a selective and concentration-dependent fashion, but does not alter ALK1-, ALK2-, ALK3-, or ALK6-induced Smad signaling [33]. SB-505124 is 3-to 5-times more potent than SB-431542.…”

Section: Identifying Lead Tgf-β Receptor Inhibitory Compounds For Inhmentioning

confidence: 95%

Transforming growth factor-β in cancer and metastasis

Jakowlew

2006

Cancer Metastasis Rev

481

386

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Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-beta are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-beta is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-beta. Loss of autocrine TGF-beta activity and/or responsiveness to exogenous TGF-beta appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-beta in addition to its tumor suppressor role. During the early phase of epithelial tumorigenesis, TGF-beta inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-beta due to inactivation of the TGF-beta signaling pathway or aberrant regulation of the cell cycle, the role of TGF-beta becomes one of tumor promotion. Resistance to TGF-beta-mediated inhibition of proliferation is frequently observed in multiple human cancers, as are various alterations in the complex TGF-beta signaling and cell cycle pathways. TGF-beta can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-beta to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-beta as a tumor suppressor and pro-oncogenic factor, members of the TGF-beta signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis.

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“…Sirt3-KO fibroblasts were treated with follistatin, an activin-binding protein, which neutralizes members of the TGF-␤ superfamily, or with a small-molecule inhibitor of TGF-␤ receptors, SB-505124 (SB) (33,34). Both inhibitors significantly reduced the expression of SMA and Smad3 in Sirt3-KO fibroblasts (Fig.…”

Section: (Ms/ms Data Of Acetylated K36 [Ac-k36] Not Shown)mentioning

confidence: 99%

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

Sundaresan

Bindu

Pillai

et al. 2016

Molecular and Cellular Biology

160

141

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Tissue fibrosis is a major cause of organ dysfunction during chronic diseases and aging. A critical step in this process is transforming growth factor ␤1 (TGF-␤1)-mediated transformation of fibroblasts into myofibroblasts, cells capable of synthesizing extracellular matrix. Here, we show that SIRT3 controls transformation of fibroblasts into myofibroblasts via suppressing the profibrotic TGF-␤1 signaling. We found that Sirt3 knockout (KO) mice with age develop tissue fibrosis of multiple organs, including heart, liver, kidney, and lungs but not whole-body SIRT3-overexpressing mice. SIRT3 deficiency caused induction of TGF-␤1 expression and hyperacetylation of glycogen synthase kinase 3␤ (GSK3␤) at residue K15, which negatively regulated GSK3␤ activity to phosphorylate the substrates Smad3 and ␤-catenin. Reduced phosphorylation led to stabilization and activation of these transcription factors regulating expression of the profibrotic genes. SIRT3 deacetylated and activated GSK3␤ and thereby blocked TGF-␤1 signaling and tissue fibrosis. These data reveal a new role of SIRT3 to negatively regulate aging-associated tissue fibrosis and discloses a novel phosphorylation-independent mechanism controlling the catalytic activity of GSK3␤.

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SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-β Type I Receptors ALK4, ALK5, and ALK7

Cited by 361 publications

References 34 publications

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

TGF-β in the Bone Microenvironment: Role in Breast Cancer Metastases

Transforming growth factor-β in cancer and metastasis

SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3β

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