Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors:  A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Li, Hong Yu; Wang, Yan; Heap, Charles R.; King, Chi Hsin R.; Mundla, Sreenivasa R.; Voss, Matthew E.; Clawson, David K.; Yan, Lei; Campbell, Robert M.; Anderson, Bryan D.; Wagner, Jill R.; Britt, Karen S.; Lu, Ku; McMillen, William T.; Yingling, Jonathan M.

doi:10.1021/jm058209g

Cited by 45 publications

(25 citation statements)

References 17 publications

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“…ALK5 inhibitor (LY-364947) is a selective, ATP-competitive inhibitor of TβRI (ALK5) kinase. It is much less potent at related kinases for TβRII and for MLK-7, a kinase in the MAP kinase signal pathway that is closely related to TGF-β RII (30). Others have reported that injection of a similar ALK5 inhibitor resulted in the specific blockade of TβRI kinase activation and subsequent repression of TGF-β–mediated growth inhibition in vivo (31).…”

Section: Resultsmentioning

confidence: 99%

Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells

Lü

Wang

Zhang

et al. 2010

The Journal of Immunology

171

163

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Whereas TGF-β is essential for the development of peripherally induced Foxp3+ regulatory T cells (iTreg cells) and Th17 cells, the intracellular signaling mechanism by which TGF-β regulates development of both cell subsets is less understood. In this study, we report that neither Smad2 nor Smad3 gene deficiency abrogates TGF-β–dependent iTreg induction by a deacetylase inhibitor trichostatin A in vivo, although the loss of the Smad2 or Smad3 gene partially reduces iTreg induction in vitro. Similarly, SMAD2 and SMAD3 have a redundant role in development of Th17 in vitro and in experimental autoimmune encephalomyelitis. In addition, ERK and/or JNK pathways were shown to be involved in regulating iTreg cells, whereas the p38 pathway predominately modulated Th17 and experimental autoimmune encephalomyelitis induction. Therefore, selective targeting of these intracellular TGF-β signaling pathways during iTreg and Th17 cell development might lead to the development of therapies in treating autoimmune and other chronic inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells

Lü

Wang

Zhang

et al. 2010

The Journal of Immunology

171

163

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“…Starting the following day, mice were treated with 5 mg/kg 1D11 anti-TGF-β antibody, 13C4 control antibody or buffer by intraperitoneal injection 3 times/week until tumor growth required sacrifice [61]. Alternatively, mice were treated with 50 mg/kg LY2109761 or 0.2 mL of vehicle by gavage twice a day, beginning on the second or third day following tumor cell inoculation, until the animals were sacrificed [62]. Body weight and bioluminescence were monitored weekly.…”

Section: Methodsmentioning

confidence: 99%

Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis

Ganapathy¹,

Ge²,

Grazioli³

et al. 2010

Mol Cancer

152

116

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BackgroundTransforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-β antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-β pathway antagonists (1D11, a mouse monoclonal pan-TGF-β neutralizing antibody and LY2109761, a chemical inhibitor of TGF-β type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR).ResultsBoth 1D11 and LY2109761 effectively blocked TGF-β-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-β stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-β. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-β antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.ConclusionsIn aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.

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“…TBS-deprotection of 4 in the presence of TBAF afforded primary alcohol 5 in quantitative yield. The treatment of 5 with MsCl and DIPEA provided mesylate 6 in 91% yield 8. Azidation of mesylate 6 with NaN 3 gave compound 7 in 85% yield 9.…”

Section: Chemistrymentioning

confidence: 99%

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

et al. 2009

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The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogs. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple 4-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles.

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Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

Cited by 45 publications

References 17 publications

Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells

Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells

Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis

Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

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