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Chemical Structure| 942183-80-4 Chemical Structure| 942183-80-4

Structure of SCH772984
CAS No.: 942183-80-4

Chemical Structure| 942183-80-4

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SCH772984 is a highly selective and ATP-competitive ERK inhibitor with IC50 values of 4 nM and 1 nM for ERK1 and ERK2, respectively. It has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations.

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Wu, Likang ; Xu, Lei ; Chen, Yu ; Xu, Guohua ; Guo, Qunfeng ; Meng, Depeng , et al.

Abstract: Background: Fibrosis is an important factor and process of ligamentum flavum hypertrophy. The expression of phosphodiesterase family (PDE) is related to inflammation and fibrosis. This article studied the expression of PDE in hypertrophic ligamentum flavum fibroblasts and investigated whether inhibition of PDE4 activity can play an anti-fibrotic effect. Methods: Samples of clinical hypertrophic ligamentum flavum were collected and patients with lumbar disc herniations as a control group. The collagenase digestion method is used to separate fibroblasts. qPCR is used to detect the expression of PDE subtypes, type I collagen (Col I), type III collagen (Col III), fibronectin (FN1) and transforming growth factor β1 (TGF-β1). Recombinant TGF-β1 was used to stimulate fibroblasts to make a fibrotic cell model and treated with Rolipram. The morphology of the cells treated with drugs was observed by Sirius Red staining. Scratch the cells to observe their migration and proliferation. WB detects the expression of the above-mentioned multiple fibrotic proteins after drug treatment. Finally, combined with a variety of signaling pathway drugs, the signaling mechanism was studied. Results: Multiple PDE subtypes were expressed in ligamentum flavum fibroblasts. The expression of PDE4A and 4B was significantly up-regulated in the hypertrophic group. Using Rolipram to inhibit PDE4 activity, the expression of Col I and TGF-β1 in the hypertrophic group was inhibited. Col I recovered to the level of the control group. TGF-β1 was significantly inhibited, which was lower than the control group. Recombinant TGF-β1 stimulated fibroblasts to increase the expression of Col I/III, FN1 and TGF-β1, which was blocked by Rolipram. Rolipram restored the increased expression of p-ERK1/2 stimulated by TGF-β1. Conclusion: The expressions of PDE4A and 4B in the hypertrophic ligamentum flavum are increased, suggesting that it is related to the hypertrophy of the ligamentum flavum. Rolipram has a good anti-fibrosis effect after inhibiting the activity of PDE4. This is related to blocking the function of TGF-β1, specifically by restoring normal ERK1/2 signal.

Keywords: Rolipram ; Phosphodiesterase ; Ligamentum Flavum hypertrophy ; ERK1/2 ; Fibrosis ; TGF-β1

Purchased from AmBeed: 61413-54-5 ; ; ;

Liu, Xuejiao ; Chen, Xiangyu ; Shi, Lin ; Shan, Qianqian ; Cao, Qiyu ; Yue, Chenglong , et al.

Abstract: Background: Glioblastoma (GBM) is a fatal brain tumor, lacking effective treatment. Epidermal growth factor receptor (EGFR) is recognized as an attractive target for GBM treatment. However, GBMs have very poor responses to the first- and second-generation EGFR inhibitors. The third-generation EGFR-targeted drug, AZD9291, is a novel and irreversible inhibitor. It is noteworthy that AZD9291 shows excellent blood–brain barrier penetration and has potential for the treatment of brain tumors. Methods: In this study, we evaluated the anti-tumor activity and effectiveness of AZD9291 in a preclinical GBM model. Results: AZD9291 showed dose-responsive growth inhibitory activity against six GBM cell lines. Importantly, AZD9291 inhibited GBM cell proliferation > 10 times more efficiently than the first-generation EGFR inhibitors. AZD9291 induced GBM cell cycle arrest and significantly inhibited colony formation, migration, and invasion of GBM cells. In an orthotopic GBM model, AZD9291 treatment significantly inhibited tumor survival and prolonged animal survival. The underlying anti-GBM mechanism of AZD9291 was shown to be different from that of the first-generation EGFR inhibitors. In contrast to erlotinib, AZD9291 continuously and efficiently inhibited the EGFR/ERK signaling in GBM cells. Conclusion: AZD9291 demonstrated an efficient preclinical activity in GBM in vitro and in vivo models. AZD9291 has been approved for the treatment of lung cancer with good safety and tolerability. Our results support the possibility of conducting clinical trials of anti-GBM therapy using AZD9291.

Keywords: GBM ; AZD9291 ; EGFR/ERK signaling pathway ; Cell proliferation

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Alternative Products

Product Details of SCH772984

CAS No. :942183-80-4
Formula : C33H33N9O2
M.W : 587.67
SMILES Code : O=C([C@H]1CN(CC(N2CCN(C3=CC=C(C4=NC=CC=N4)C=C3)CC2)=O)CC1)NC5=CC6=C(NN=C6C7=CC=NC=C7)C=C5
MDL No. :MFCD28144700
InChI Key :HDAJDNHIBCDLQF-RUZDIDTESA-N
Pubchem ID :24866313

Safety of SCH772984

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Related Pathways of SCH772984

MAPK

Isoform Comparison

Biological Activity

Target
  • ERK2

    ERK2, IC50:1 nM

  • ERK1

    ERK1, IC50:4 nM

In Vitro:

Cell Line
Concentration Treated Time Description References
M233 500 nM 24 h inhibition of pRSK, rebound in pERK1/2, increase in pMEK Mol Cancer. 2014 Aug 20;13:194.
M238 500 nM 24 h inhibition of pRSK and pERK1/2, reduction in pAKT levels, slight induction of pMEK Mol Cancer. 2014 Aug 20;13:194.
M262 500 nM 24 h inhibition of pRSK and pERK1/2, reduction in pAKT levels Mol Cancer. 2014 Aug 20;13:194.
M381 500 nM 24 h induction of pMEK and pERK1/2, no change in pRSK Mol Cancer. 2014 Aug 20;13:194.
M409 500 nM 24 h inhibition of pRSK, reduction in pERK1/2, increase in pMEK Mol Cancer. 2014 Aug 20;13:194.
Hep3B cells 10 μM 24 h SCH772984 suppressed the LAGE3 upregulation-induced proliferation, migration, and invasion of Hep3B cells. Cell Mol Biol Lett. 2021 Nov 27;26(1):49.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice Breast cancer xenograft model Intraperitoneal injection 25 mg/kg Twice daily for 2 weeks To evaluate the inhibitory effect of ERK1/2 inhibitor SCH772984 on breast cancer metastasis and CTC formation. The results showed that SCH772984 significantly reduced CTC numbers and lung metastasis. J Exp Clin Cancer Res. 2022 Oct 13;41(1):301

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

1.70mL

0.34mL

0.17mL

8.51mL

1.70mL

0.85mL

17.02mL

3.40mL

1.70mL

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