NVP-ADW742

 

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Biological Activity

Description	NVP-ADW742 is an IGF-1R inhibitor with IC50 of 0.17 μM, >16-fold more potent against IGF-1R than InsR; little activity to HER2, PDGFR, VEGFR-2, Bcr-Abl and c-Kit.
Targets	IGF-1R
IC50	0.17 μM [1]
In vitro	NVP-ADW742 exhibits a 6-fold greater selectivity for IGF-1R versus InsR with IC50 of 2.8 μM; minimal inhibitory activity against c-Kit, HER1, PDGFR, VEGFR2, or Bcr-Abl p210 with IC50 greater than 5 μM. NVP-ADW742 significantly inhibits the serum-stimulated cell proliferation in a variety of tumor cell lines in dose-dependent manner, with IC50 values of 0.1-0.5 μM for the multiple myeloma (MM) cell lines, and the antitumor effects on MM cells can not be overcome by the co-culture with BMSCs. NVP-ADW742 also abrogates the responsiveness of tumor cells to IL-6 in the presence of serum. In addition, NVP-ADW742 is active against MM cell lines with resistance to conventional (cytotoxic chemotherapy, dexamethasone) or investigational (thalidomide, CC-5013, TRAIL/Apo2L, PS-341) anticancer agents, as well as primary tumor cells from MM patients with multi-drug-resistant disease. NVP-ADW742 decreases the production of VEGF by tumor cells and bone marrow stromal cells, and suppresses the IGF-1-induced secretion of VEGF by various tumor types such as thyroid cancer cells or MM cells. IGF-1R inhibition by NVP-ADW742 (0.75 μM) sensitizes MM cells or prostate cancer cells to other anticancer agents such as doxorubicin, melphalan, dexamethasone, TRAIL/Apo2L, or PS-341. [1]
In vivo	Administration of NVP-ADW742 at 10 mg/kg twice daily significantly inhibits tumor growth, prolongs survival, and enhances the antitumor effect of cytotoxic chemotherapy melphalan in the mice model of diffuse MM. [1]
Features

Protocol(Only for Reference)

Kinase Assay: ^[1]

Cellular kinase activity assay

The IC50 value for the effect of NVP-ADW742 on the autophosphorylation of IGF-1R is determined at the cellular level in the presence of increasing concentrations of NVP-ADW742, using 96-well “Capture ELISAs” assays. Briefly, NWT-21 cells are seeded into 96-well tissue culture plates in complete growth medium and grown to 70-80% confluency, and are then starved for 24 hours in 0.5% FCS medium. Subsequently, cells are incubated for 90 minutes in the presence of NVP-ADW742 followed by the stimulation with of IGF-I (10 ng/mL) for 10 minutes at 37 °C. Subsequently, the cells are washed twice with ice-cold PBS and lysed at 4 °C with 50 μL/well RIPA-buffer (50 mM Tris-HCl, pH 7.2, 120 mM NaCl, 1 mM EDTA, 6 mM EGTA, 1% NP-40, 20 mM NaF, 1 mM benzamidine, 15 mM sodium pyrophosphate, 1 mM PMSF and 0.5 mM Na3VO4). The lysates from each experiment are then transferred to black ELISA plates precoated with capture antibodies specific for IGF-1R. After capture by the antibodies, lysates are mixed with 40 μL of an alkaline phosphatase (AP) labelled anti-phosphotyrosine Ab (PY20(AP) diluted to 0.2 μg/mL in RIPA buffer, and incubated overnight at 4 °C. After washing (PBST) and incubation for 45 minutes at RT with the luminescent AP-substrate CDPStar RTU with Emerald II (90 μL/well), luminescence is measured using a Packard Top Count Scintillation Counter.

Cell Assay: ^[1]

Cell lines	MM-1S, MM-1R, RPMI-8226/S, OPM-1, OCI-My5, SKMM2, KMS-12-BM, XG-1, L363, S6B45 cells and et al.
Concentrations	Dissolved in DMSO, final concentrations ~ 10 μM
Incubation Time	48 hours
Method	Cells are exposed to various concentrations of NVP-ADW742 for 48 hours in the presence or absence of serum. Cell survival is examined using MTT assay.

Animal Study: ^[1]

Animal Models	Male SCID/NOD mice injected i.v. with MM-1S-Luc+ human MM cells
Dosages	10 mg/kg twice daily
Administration	Injection i.p. or oral gavage

1

References

Chemical Information

Download NVP-ADW742 SDF

Chemical Name	5-(3-(benzyloxy)phenyl)-7-((1r,3r)-3-(pyrrolidin-1-ylmethyl)cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.45358	4.5358	9.0716	-

Customer Reviews (1)

Click to enlarge	Rating
	Source	Biomaterials, 2013, 34(38):9737-46 . NVP-ADW742 purchased from Selleck
	Method	Western blot
	Cell Lines	SKOV3/T cells
	Concentrations	2 uM
	Incubation Time	24 h
	Results	As shown in Fig. A, both NVP-ADW742 and shRNA-HER3 transfection could dramatically inhibit SKOV3/T cell proliferation, suggesting that both IGF-1R and HER3 contributed to cell proliferation in SKOV3/T cells and IGF-1R seems to show greater importance than HER3. As shown in Fig. 4B, the S-phase was about 9% (HER3 knockdown and IGF-1R inhibition) contrasting to the value of 16% in SKOV3/T treated with NVP-ADW742 (IGF-1R inhibition), and that of 21% in HER3 knockdown cells and 29% (control, untreated) in SKOV3/T.

Product Citations (1)

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  IGF-1R and ErbB3/HER3 contribute to enhanced proliferation and carcinogenesis in trastuzumab-resistant ovarian cancer model. [Jia Y, et al. Biochem Biophys Res Commun 2013;436(4):740-5]

  
  PubMed: 23792093