Identification of Novel Inhibitors of the Transforming Growth Factor β1 (TGF-β1) Type 1 Receptor (ALK5)

Callahan, James F.; Burgess, Joelle L.; Fornwald, James A.; Gaster, Laramie M.; Harling, John D.; Harrington, Frank P.; Heer, Jag; Kwon, Chet; Lehr, Ruth; Mathur, Ashwini; Olson, Beth; Weinstock, Joseph; Laping, Nicholas J.

doi:10.1021/jm010493y

Cited by 294 publications

(224 citation statements)

References 14 publications

Supporting

Mentioning

217

Contrasting

Order By: Relevance

“…Moreover, phosphorylation and nuclear localization of Smad2 induced by TGF-β, activin, or Nodal signaling were observed in undifferentiated human ES cells, and decreased upon early differentiation [21]. Inhibition of TGF-β/activin/ Nodal signaling by SB-431542, a chemical inhibitor of the kinases of type I receptors for TGF-β/activin/Nodal [22,23], resulted in decreased expression of the markers of undifferentiated states [21,24]. Xiao et al [25] also found that activin is able to support long-term feederfree culture and maintenance of pluripotency of human ES cells possibly by inducing the expression of Oct-4 and Nanog, which was shown by microarray analysis.…”

Section: Tgf-β Family Signaling In the Maintenance Of Pluripotency Anmentioning

confidence: 99%

Roles of TGF-β family signaling in stem cell renewal and differentiation

2008

View full text Add to dashboard Cite

Section: Tgf-β Family Signaling In the Maintenance Of Pluripotency Anmentioning

confidence: 99%

Roles of TGF-β family signaling in stem cell renewal and differentiation

2008

View full text Add to dashboard Cite

“…The invasion assay was conducted as described (15). EGF (60 ng/mL; Sigma) or TGF-b1 (2.5 ng/mL; R&D Systems Inc.) were used as chemoattractants, and SB-431542 (20 mmol/L; Sigma) was used as a specific TGF-b1 signaling inhibitor by blocking TbRI kinase activity (16). Cells were allowed to migrate and invade into growth factor-reduced Matrigel for 15 days, stained with 4 mmol/L calcein-acetoxymethyl ester (Invitrogen), and visualized by confocal microscopy (Leica TCS SP2 confocal microscope) using a Â10 objective.…”

Section: Cell-inverted Invasion Assaymentioning

confidence: 99%

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

Muinelo‐Romay

Colás

Barbazán

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Endometrial cancer is among the three most common cancers in females in industrialized countries. In the majority of cases, the tumor is confined to the uterus at the time of diagnosis and presents a good prognosis. However, after primary surgery, 15% to 20% of these tumors recur and have limited response to systemic therapy. We carried out gene expression profiling of high-risk recurrence endometrial cancers to identify new therapeutic approaches targeting the molecular pathways involved in the acquisition of an aggressive tumor phenotype. A microarray gene-expression analysis on a total of 51 human endometrial carcinomas revealed 77 genes specifically altered in high-risk recurrence tumors (P < 0.001). The bioinformatics analysis of gene-gene interactions and molecular relationships among these genes pointed to a prominent role for TGFb1 signaling in the acquisition of an aggressive phenotype. We further showed that TGF-b1 has a principal role at the initiation of endometrial carcinoma invasion through the promotion of the epithelial to mesenchymal transition that leads to the acquisition of an invasive phenotype in HEC-1A and RL95-2 cells. Impairment of this initial step with SB-431542, a specific TGF-b1 inhibitor, precluded further persistent endometrial carcinoma invasion. In conclusion, we showed that the characterization of the molecular changes associated with the acquisition of an aggressive phenotype represents a realistic strategy for the rational identification and characterization of new potential therapeutic targets in an effort to improve the clinical management and the outcome of high-risk endometrial cancer patients. Mol Cancer Ther; 10(8); 1357-66. '2011 AACR.

show abstract

“…Previous studies have shown that individual TbRI kinase inhibitors have different half-maximal inhibitory concentration values or different dissociation constant values for each receptor. 12,19,20 Such an inhibition profile may be due to pharmacological differences between each compound, as well as differences in receptor expression in the assayed cells. Similarly to the results of A204 cells, Ki26894 broadly suppressed the upregulation of p21 induced by myostatin, activin, and TGF-b1 in HaCaT cells.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19][20] A204 human rhabdomyosarcoma cells or HEK293 human embryonic kidney cells were transfected with pGL3-(CAGA) 12 luciferase, a TGF-b-sensitive Smad-responsive luciferase reporter gene. 21 Stimulation of these cells with recombinant myostatin, activin A, or TGF-b1 caused a significant increase in luciferase activity above the basal level (A204: Figure 1a-c; HEK293: Figure 1d-f).…”

Section: Tbri Kinase Inhibitors Broadly Suppress the In-vitro Transcrmentioning

confidence: 99%

See 1 more Smart Citation

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

Ohsawa

Okada

Nishimatsu

et al. 2012

Laboratory Investigation

View full text Add to dashboard Cite

Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3 P104L ) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-b) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-b type I receptor (TbRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-b1, -b2, and -b3 signaling. Here, we show that a TbRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-b1, as well as CAV3 P104L . Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3 P104L mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-b family members in muscle. These data indicate that both TGF-b-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TbRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-b signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.

show abstract

Identification of Novel Inhibitors of the Transforming Growth Factor β1 (TGF-β1) Type 1 Receptor (ALK5)

Cited by 294 publications

References 14 publications

Roles of TGF-β family signaling in stem cell renewal and differentiation

Roles of TGF-β family signaling in stem cell renewal and differentiation

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

Contact Info

Product

Resources

About