产品号 #73632_C
Activin/Nodal/TGFβ 通路抑制剂；抑制 ALK2
总览
DMH1（dorsomorphin homolog 1）是激活素受体样激酶2（ALK2；IC₅₀=13-108 nM）的选择性抑制剂，ALK2是 I 型骨形态发生蛋白（BMP）受体（Hao et al.; Mohedas et al.）。DMH1对ALK4、ALK5、AMPK、KDR（VEGFR2）或PDGFRβ没有可检测到的抑制作用，尽管它在nM浓度下抑制ALK1和ALK3（Hao et al.; Mohedas et al.）。
分化
·诱导小鼠胚胎干细胞分化为心肌细胞祖细胞（Ao et al.）。
·诱导人诱导多能干细胞分化为表达SOX1和PAX6的神经前体细胞（Neely et al.）。
·在斑马鱼早期胚胎中，使胚胎轴背侧化，但不破坏血管生成过程（Hao et al. 2010）。
癌症研究
·抑制非小细胞肺癌细胞体外生长、迁移和侵袭，并减弱体内异种移植肺肿瘤的生长（Hao et al. 2014）。
·抑制化疗药物诱导的自噬反应（Sheng et al.）。
细胞类型
癌细胞及细胞系，心肌细胞，PSC衍生，神经细胞，PSC衍生，神经干/祖细胞，多能干细胞
种属
人，小鼠，非人灵长类，其它细胞系，大鼠
应用
分化
研究领域
癌症，干细胞生物学
CAS 编号
1206711-16-1
化学式
C₂₄H₂₀N₄O
纯度
≥98%
通路
Activin/Nodal/TGFβ
靶点
ALK2
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Applications
This product is designed for use in the following research area(s) as part of the highlighted workflow stage(s). Explore these workflows to learn more about the other products we offer to support each research area.
Resources and Publications
Educational Materials (5)
Publications (7)
DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline) inhibits chemotherapeutic drug-induced autophagy. Acta pharmaceutica Sinica. B 2015 JUL
Abstract
Our previous work found that DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl]quinoline) was a novel autophagy inhibitor. Here, we aimed to investigate the effects of DMH1 on chemotherapeutic drug-induced autophagy as well as the efficacy of chemotherapeutic drugs in different cancer cells. We found that DMH1 inhibited tamoxifen- and cispcis-diaminedichloroplatinum (II) (CDDP)-induced autophagy responses in MCF-7 and HeLa cells, and potentiated the anti-tumor activity of tamoxifen and CDDP for both cells. DMH1 inhibited 5-fluorouracil (5-FU)-induced autophagy responses in MCF-7 and HeLa cells, but did not affect the anti-tumor activity of 5-FU for these two cell lines. DMH1 itself did not induce cell death in MCF-7 and HeLa cells, but inhibited the proliferation of these cells. In conclusion, DMH1 inhibits chemotherapeutic drug-induced autophagy response and the enhancement of efficacy of chemotherapeutic drugs by DMH1 is dependent on the cell sensitivity to drugs.
DMH1, a small molecule inhibitor of BMP type i receptors, suppresses growth and invasion of lung cancer. PloS one 2014 JAN
Abstract
The bone morphogenetic protein (BMP) signaling cascade is aberrantly activated in human non-small cell lung cancer (NSCLC) but not in normal lung epithelial cells, suggesting that blocking BMP signaling may be an effective therapeutic approach for lung cancer. Previous studies demonstrated that some BMP antagonists, which bind to extracellular BMP ligands and prevent their association with BMP receptors, dramatically reduced lung tumor growth. However, clinical application of protein-based BMP antagonists is limited by short half-lives, poor intra-tumor delivery as well as resistance caused by potential gain-of-function mutations in the downstream of the BMP pathway. Small molecule BMP inhibitors which target the intracellular BMP cascades would be ideal for anticancer drug development. In a zebrafish embryo-based structure and activity study, we previously identified a group of highly selective small molecule inhibitors specifically antagonizing the intracellular kinase domain of BMP type I receptors. In the present study, we demonstrated that DMH1, one of such inhibitors, potently reduced lung cell proliferation, promoted cell death, and decreased cell migration and invasion in NSCLC cells by blocking BMP signaling, as indicated by suppression of Smad 1/5/8 phosphorylation and gene expression of Id1, Id2 and Id3. Additionally, DMH1 treatment significantly reduced the tumor growth in human lung cancer xenograft model. In conclusion, our study indicates that small molecule inhibitors of BMP type I receptors may offer a promising novel strategy for lung cancer treatment.
Development of an ALK2-biased BMP type I receptor kinase inhibitor. ACS chemical biology 2013 JAN
Abstract
The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and the normal and pathophysiologic remodeling of tissues. Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases. Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-β and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity, and function. LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva. These findings represent a significant step toward developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family. Such inhibitors would provide greater resolution as probes of physiologic function and improved selectivity against therapeutic targets.
更多信息
| Species | Human, Mouse, Non-Human Primate, Other, Rat |
|---|---|
| Cas Number | 1206711-16-1 |
| Chemical Formula | C₂₄H₂₀N₄O |
| Purity | ≥ 98% |
| Target | ALK2 |
| Pathway | Activin/Nodal/TGFβ |
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