SCH 51344

MTH1 inhibitor CAS# 171927-40-5

SCH 51344

Catalog No. BCC5613----Order now to get a substantial discount!

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Quality Control of SCH 51344

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Chemical structure

SCH 51344

3D structure

Chemical Properties of SCH 51344

Cas No. 171927-40-5 SDF Download SDF
PubChem ID 9995890 Appearance Powder
Formula C16H20N4O3 M.Wt 316.35
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in DMSO
Chemical Name 2-[2-[(6-methoxy-3-methyl-2H-pyrazolo[3,4-b]quinolin-4-yl)amino]ethoxy]ethanol
SMILES CC1=C2C(=C3C=C(C=CC3=NC2=NN1)OC)NCCOCCO
Standard InChIKey YWEGXZZAORIRQR-UHFFFAOYSA-N
Standard InChI InChI=1S/C16H20N4O3/c1-10-14-15(17-5-7-23-8-6-21)12-9-11(22-2)3-4-13(12)18-16(14)20-19-10/h3-4,9,21H,5-8H2,1-2H3,(H2,17,18,19,20)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of SCH 51344

DescriptionPotent MTH1 inhibitor (Kd = 49 nM). Inhibits Ras-induced malignant transformation and increases α-actin promoter-driven CAT activity in Ras-transformed cells. Has no effect on Ras-induced ERK and JNK activation. Inhibits Ras-induced membrane ruffling in REF-52 fibroblasts and blocks anchorage-independent growth of Ras-transformed tumor cell lines. Also induces DNA damage in SW480 colon cancer cells.

SCH 51344 Dilution Calculator

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SCH 51344 Molarity Calculator

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Preparing Stock Solutions of SCH 51344

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.1611 mL 15.8053 mL 31.6106 mL 63.2211 mL 79.0264 mL
5 mM 0.6322 mL 3.1611 mL 6.3221 mL 12.6442 mL 15.8053 mL
10 mM 0.3161 mL 1.5805 mL 3.1611 mL 6.3221 mL 7.9026 mL
50 mM 0.0632 mL 0.3161 mL 0.6322 mL 1.2644 mL 1.5805 mL
100 mM 0.0316 mL 0.1581 mL 0.3161 mL 0.6322 mL 0.7903 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on SCH 51344

Kd: 49 nM

SCH 51344 is a potent MTH1 inhibitor.

MTH1, also known as NUDT1, is a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells. RAS possessed interaction with multiple targets in the cell and regulates at least two signaling pathways, one controlling extracellular signal-regulated kinase (ERK) activation and the other regulating membrane ruffling formation. These two pathways could synergistically cause transformation.

In vitro: SCH 51344 inhibits Ras-accelerated malignant transformation and increases α-actin promoter-stimulated CAT activity in Ras-transformed cells. SCH 51344 has quite little effect on Ras-induced ERK and JNK activation. SCH 51344 inhibits Ras-accelerated membrane ruffling in REF-52 fibroblasts and abolishes anchorage-independent growth of Ras-mediated tumor cell lines. SCH 51344 also induces DNA damage in SW480 colon cancer cells [1,2].

SCH 51344 specifically inhibits membrane ruffling stimulated by activated forms of H-RAS, K-RAS, N-RAS, and RAC. Fibroblast cells treated with this compound had very little effect on activation of ERK and JUN kinase activities mediated by RAS. SCH 51344 was an effective inhibitor of the anchorage-independent growth of Rat-2 fibroblast cells (transformed by the three forms of oncogenic RAS and RAC V12). These facts suggest that a critical component inhibited by SCH 51344 existed in the membrane ruffling pathway downstream from RAC and indicated that this may be an effective approach targeting this pathway to inhibiting transformation by RAS and other oncogenes [1,2].

In vivo: So far, no study in vivo has been conducted.

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Walsh AB, Dhanasekaran M, Bar-Sagi D, Kumar CC.  SCH 51344-induced reversal of RAS-transformation is accompanied by the specific inhibition of the RAS and RAC-dependent cell morphology pathway. Oncogene. 1997 Nov 20;15(21):2553-60.
[2].  Kumar CC, Ohashi K, Nagata K, Walsh A, Bar-Sagi D, Mizuno K. SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway. Ann N Y Acad Sci. 1999; 886: 122-31.

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References on SCH 51344

SCH 51344-induced reversal of RAS-transformation is accompanied by the specific inhibition of the RAS and RAC-dependent cell morphology pathway.[Pubmed:9399643]

Oncogene. 1997 Nov 20;15(21):2553-60.

RAS interacts with multiple targets in the cell and controls at least two signaling pathways, one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling formation. These two pathways appear to act synergistically to cause transformation. SCH 51344 is a pyrazolo-quinoline derivative identified based on its ability to derepress transformation sensitive alpha-actin promoter in RAS-transformed cells. Previous studies have shown that SCH 51344 is a potent inhibitor of RAS-transformation. However, SCH 51344 had very little effect on the activities of proteins in the ERK pathway, suggesting that it inhibits RAS-transformation by a novel mechanism. In this study, we show that SCH 51344 specifically blocks membrane ruffling induced by activated forms of H-RAS, K-RAS, N-RAS and RAC. Treatment of fibroblast cells with this compound had very little effect on RAS-mediated activation of ERK and JUN kinase activities. SCH 51344 was effective in inhibiting the anchorage-independent growth of Rat-2 fibroblast cells transformed by the three forms of oncogenic RAS and RAC V12. These results indicate that SCH 51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and suggest that targeting this pathway may be an effective approach to inhibit transformation by RAS and other oncogenes.

SCH 51344 inhibits ras transformation by a novel mechanism.[Pubmed:7585559]

Cancer Res. 1995 Nov 1;55(21):5106-17.

A pyrazolo-quinoline compound, 6-methoxy-4-[2-[(2-hydroxyethoxyl)-ethyl]amino]-3-methyl-1M-pyrazo lo [3,4-b]quinoline (SCH 51344), was identified based on its ability to derepress human smooth muscle alpha-actin promoter activity in ras-transformed cells. In this study, we show that SCH 51344 reverts several key aspects of ras transformation, such as morphological changes, actin filament organization, and anchorage-independent growth, and also inhibits Val-12 Ras-induced maturation of Xenopus oocytes. SCH 51344 is also a potent inhibitor of the anchorage-independent growth of human tumor lines known to contain multiple genetic alterations in addition to activated ras genes. We have sought to determine whether SCH 51344 disrupts the signaling pathway that activates mitogen-activated protein (MAP) kinase or extracellular signal-regulated kinase (ERK) in normal and ras-transformed fibroblast cells. NIH 3T3 cells transformed by different oncogenes, which have products that participate at different steps of the Ras signaling pathway, were tested in a soft-agar colony formation assay to determine which step of the pathway is inhibited by SCH 51344. Our results indicate that SCH 51344 inhibits the ability of v-abl, v-mos, H-ras, v-raf, and mutant active MAP kinase kinase-transformed NIH 3T3 cells to grow in soft agar. Only v-fos-transformed cells were found to be resistant to the treatment of SCH 51344. SCH 51344 treatment had very little effect, if any, on the activation of MAP kinase kinase, MAP kinase, and p90RSK activity in response to growth factor stimulation. Treatment of ras-transformed cells with SCH 51344 led to stimulation of serum response factor DNA binding activity and activation of serum response element-dependent gene transcription, accounting for its ability to activate alpha-actin promoter activity in ras-transformed cells. Our results indicate that SCH 51344 inhibits ras transformation by a novel mechanism and acts at a point either downstream or parallel to extracellular signal-regulated kinase-dependent Ras signaling pathway.

SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway.[Pubmed:10667210]

Ann N Y Acad Sci. 1999;886:122-31.

RAS interacts with multiple targets in the cell and controls at least two signaling pathways, one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling formation. These two pathways appear to act synergistically to cause transformation. Human smooth muscle alpha-actin promoter is repressed in RAS-transformed cells and derepressed in revertant cell lines, suggesting that it is a sensitive marker to follow phenotypic changes in fibroblast cells. SCH 51344 is a pyrazoloquinoline derivative identified on the basis of its ability to derepress alpha-actin promoter in RAS-transformed cells. Previous studies have shown that SCH 51344 is a potent inhibitor of RAS transformation. However, SCH 51344 had very little effect on the activities of proteins in the ERK pathway, suggesting that it inhibits RAS transformation by a novel mechanism. Recently, we have demonstrated that SCH 51344 specifically blocks membrane ruffling induced by activated forms of H-RAS, K-RAS, N-RAS, and RAC. Treatment of fibroblast cells with this compound had very little effect on RAS-mediated activation of ERK and JUN kinase activities. SCH 51344 was effective in inhibiting the anchorage-independent growth of Rat-2 fibroblast cells transformed by the three forms of oncogenic RAS and RAC V12. These results indicate that SCH 51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and suggest that targeting this pathway may be an effective approach to inhibiting transformation by RAS and other oncogenes.

Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.[Pubmed:24695225]

Nature. 2014 Apr 10;508(7495):222-7.

Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.

Description

Potent MTH1 inhibitor

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