DMH-1

[Description]:

DMH-1 is a potent and selective BMP inhibitor with IC50s of 27/107.9/<5/47.6 nM for ALK1/ALK2/ALK3/ALK6, respectively.

[Related Catalog]:

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> TGF-beta/Smad >> TGF-β Receptor

Research Areas >> Cancer

[Target]

IC50: 27 nM (ALK1), 107.9 nM (ALK2), <5 nM (ALK3), 47.6 nM (ALK6)[1]

[In Vitro]

DMH-1 (0.5 μM) induces regulation of OCT4, Nanog, and PAX6 protein expression. DMH-1 significantly reduces the percentage of cells expressing the pluripotency marker proteins OCT4 and Nanog in both SM3 and CA6 cells. PAX6 expression is significantly up-regulated by day 5 and day 7 in CA6 and SM3 cells, respectively. DMH-1 induces regulation of pluripotency and neural precursor marker mRNAs. PAX6 can regulate the expression of SOX1 independently by manipulating the DMH-1 concentration during the neural induction of hiPSCs[2]. DMH-1 (5 μM and 10 μM) inhibits CDDP-induced autophagy in HeLa cells and enhances the ability of CDDP to reduce HeLa cell viability, inhibits tamoxifen-induced autophagy in MCF-7 cells and enhances the ability of tamoxifen to reduce MCF-7 cell viability, inhibits 5-FU-induced autophagy in both MCF-7 and HeLa cells but does not affect the inhibitory effects of 5-FU on MCF-7 and HeLa cell viability. DMH-1 enhances the apoptotic induction effects of CDDP on HeLa cells after 24 h treatment. DMH-1 inhibits HeLa and MCF-7 cell proliferation[3]. DMH-1 (20 μM) reduces the canonical phosphorylation of Smads 1,5 and 9. DMH-1 in combination with Cisplatin significantly decreases Ki-67 positive staining in the OVCAR8 cells. DMH-1 (20 µM) upregulates JAG1, reduces CYP1B1 and increases HAPLN1 expression in both OVCAR8 and NCI-RES cells[4].

[In Vivo]

DMH1 (5 mg/kg, i.p.) treatment significantly reduces the tumor growth in human lung cancer xenograft model[5].

[Cell Assay]

Cells are seeded in 96-well plates and treated with different drugs for appropriate time. Then 5 mg/mL MTT is added and incubated for 4 h at 37°C. Medium is then removed and 200 μL of DMSO is added to dissolve the crystal. Absorbance is measured at a wavelength of 490 nm with a plate reader.

[Animal admin]

Sub-confluent A549 cells are trypsinized and then suspended in serum free RPMI 1640 medium. The cell suspension (1×106 cells in 100 µL medium for each injection) is injected subcutaneously into both the right and left flanks of eight-week old NOD SCID mice (n=5 for each group). Mice are given Intraperitoneal (i.p.) injection of the vehicle (12.5% 2-hydroxypropyl-β-cyclodextrin) or 5 mg/kg DMH1 every other day. The tumor sizes are measured with a vernier caliper from the sixth day to the fourth week after tumor implantation. The tumor volume (V) is calculated according to the formulation: Volume=(width)2×length/2. The tumor tissues are dissected at the end of study, and are sectioned and stained with H & E, and for immunohistochemical analysis.

[References]

[1]. Engers DW, et al. Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of mL347 as an ALK2 versus ALK3 selective mLPCN probe. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52.

[2]. Neely MD, et al. DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and SOX1 expression during neural induction. ACS Chem Neurosci. 2012 Jun 20;3(6):482-91.

[3]. Sheng Y, et al. DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline) inhibits chemotherapeutic drug-induced autophagy. Acta Pharm Sin B. 2015 Jul;5(4):330-6.

[4]. Hover LD, et al. Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth. Cancer Lett. 2015 Nov 1;368(1):79-87.

[5]. Hao J, et al. DMH1, a small molecule inhibitor of BMP type i receptors, suppresses growth and invasion of lung cancer. PLoS One. 2014 Mar 6;9(6):e90748.

[Related Small Molecules]

SB431542 | Galunisertib (LY2157299) | A 83-01 | LY2109761 | LDN193189 | RepSox | SB525334 | Vactosertib (TEW-7197) | GW788388 | LY364947 | SB505124 | LY3200882 | H-Leu-Ser-Lys-Leu-NH2 trifluoroacetate salt | ITD-1 | K 02288

[ Density]:
1.2±0.1 g/cm3

[ Molecular Formula ]:
C₂₄H₂₀N₄O

[ Molecular Weight ]:
380.442

[ Exact Mass ]:
380.163696

[ PSA ]:
52.31000

[ LogP ]:
3.62

[ Appearance of Characters ]:
light yellow to orange

[ Index of Refraction ]:
1.672

[ Storage condition ]:
Store at +4°C

[ Water Solubility ]:
DMSO: soluble5mg/mL, clear (warmed)

Click to get detail MSDS

[ Symbol ]:

GHS06

[ Signal Word ]:
Danger

[ Hazard Statements ]:
H301

[ Precautionary Statements ]:
P301 + P310

[ Hazard Codes ]:
T

[ Risk Phrases ]:
25

[ Safety Phrases ]:
45

[ RIDADR ]:
UN 2811 6.1 / PGIII

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