Amuvatinib (MP-470)

 

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Biological Activity

Description	Amuvatinib (MP-470) is a potent and multi-targeted inhibitor of c-Kit, PDGFRα and Flt3 with IC50 of 10 nM, 40 nM and 81 nM, respectively. Phase 2.
Targets	c-KitD816H	PDGFRαV561D	Flt3D835Y
IC50	10 nM	40 nM	81 nM [1]
In vitro	The hydrochloride salt of MP-470 also inhibits several mutants of c-Kit, including c-KitD816V, c-KitD816H, c-KitV560G, and c-KitV654A, as well as a Flt3 mutant (Flt3D835Y) and two PDGFRα mutants (PDGFRαV561D and PDGFRαD842V), with IC50 of 10 nM to 8.4 μM. MP-470 potently inhibits the proliferation of OVCAR-3, A549, NCI-H647, DMS-153, and DMS-114 cells, with IC50 of 0.9 μM–7.86 μM. [1] MP-470 also inhibits c-Kit and PDGFRα, with IC50 values of 31 μM and 27 μM, respectively. MP-470 demonstrates potent cytotoxicity against MiaPaCa-2, PANC-1, and GIST882 cells, with IC50 of 1.6 μM to 3.0 μM. MP-470 also binds to and inhibits several c-Kit mutants, including c-KitK642E, c-KitD816V, and c-KitK642E/D816V. [2] In MDA-MB-231 cells, MP-470 (1 μM) inhibits tyrosine phosphorylation of AXL. [3] In LNCaP and PC-3, but not DU145 cells, MP-470 exhibits cytotoxicity with IC50 of 4 μM and 8 μM, respectively, and induces apoptosis at 10 μM. In LNCaP cells, MP-470 (10 μM) elicits G1 arrest and decreases phosphorylation of Akt and ERK1/2. [4] In SF767 cells, MP-470 (10 μM) inhibits c-Met phosphorylation and sensitizes cells to radiation. In combination with radiation, MP-470 (10 μM) inhibits glycogen synthase kinase (GSK)3β activity, induces apoptosis, and disrupts the repair of dsDNA breaks probably through suppression of Rad51. [5] [6]
In vivo	In mice xenograft models of HT-29, A549, and SB-CL2 cells, MP-470 (10 mg/kg–75 mg/kg via i.p. or 50 mg/kg–200 mg/kg via p.o.) inhibits tumor growth. [1] In mice bearing LNCaP xenograft, MP-470 (20 mg/kg) combined with Erlotinib significantly induces tumor growth inhibition (TGI). [4]
Features

Protocol(Only for Reference)

Kinase Assay: ^[2]

Kinase inhibition assay of c-Kit and PDGFRα	For the testing of inhibitory activity against c-Kit and PDGFRα, enzymes are incubated with varying concentrations of MP-470 and radiolabeled γ-32P-ATP. After 30 min, the reaction mixtures are electrophoresed on an acrylamide gel and autophosphorylation, quantitated by the amount of radioactivity incorporated into the enzyme, is assayed.

Cell Assay: ^[2]

Cell lines	MiaPaCa-2, PANC-1, and GIST882 cells
Concentrations	0–30 μM, dissolved in DMSO
Incubation Time	96 hours
Method	Cells are plated at a density of 2 × 103 to 1 × 104 cells per well in 100 μL medium on day 0 in 96-well Falcon microtitier plates. On day 1, ten μL of serial dilutions of MP-470 are added to the plates in quadruplicates. After incubation for 4 days, the cells are fixed with 10% Trichloroacetic acid solution. Subsequently, they are labeled with 0.04% Sulforhodamine B (SRB) in 1% acetic acid. After multiple washes to remove the excess dye, 100 μL of 50 mM Tris solution is added to each well in order to dissolve the dye. The absorbance of each well is read on a plate reader at 570 nm. Date are expressed as the percentage of survival of control calculated from the absorbance corrected for background absorbance. The surviving percent of cells is determined by dividing the mean absorbance values of the monoclonal antibody by mean absorbance values of the control and multiplying by 100.

Animal Study: ^[1]

Animal Models	Mice (athymic nude) xenograft models of HT-29, A549, and SB-CL2 cells
Dosages	10 mg/kg–75 mg/kg (i.p.) or 50 mg/kg–200 mg/kg (p.o.)
Administration	Oral gavage (qd5 × 3 weeks) or intraperitoneal injection (qd5 × 2 weeks)
Solubility	30% PEG400/0.5% Tween80/5% propylene glycol, 30 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00504205	Terminated	Lymphoma|Unspecified Adult Solid Tumor, Protocol Specific	National Cancer Institute (NCI)|Astex Pharmaceuticals	2007-05
NCT00894894	Completed	Solid Tumors	Astex Pharmaceuticals	2007-05	Phase 1
NCT00881166	Completed	Malignant Disease	Astex Pharmaceuticals	2007-11	Phase 1
NCT01357395	Active, not recruiting	Small Cell Lung Carcinoma	Astex Pharmaceuticals	2011-05	Phase 2

Chemical Information

Download Amuvatinib (MP-470) SDF

Chemical Name

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.44751	4.4751	8.9502	13.4253

Customer Reviews (1)

Click to enlarge	Rating
	Source	Dr. Yong-Weon Yi from Georgetown University Medical Center.Amuvatinib (MP-470) purchased from Selleck
	Method	MTT assays
	Cell Lines	UWB1.289 cells, A2780Cis cells
	Concentrations	0-10 μM
	Incubation Time	72 h
	Results	MP-470 treatments reduced UWB1.289 cells and A2780Cis cells growth in a dose-dependent manner.

Product Citations (2)

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  Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. [Zhang Z, et al. Nat Genet 2012;44(8):852-60]

  
  PubMed: 22751098


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  AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. [Asiedu MK, et al. Oncogene 2013;10.1038/onc]

  
  PubMed: 23474758