AMG 925 (FLX925; AMG925)

Alias: FLX 925; AMG925; FLX925; FLX-925; AMG-925; AMG 925

Cat No.:V0587 Purity: ≥98%

COA Product Data Instructions for use SDS

AMG 925 (also called FLX-925; AMG-925) is a novel, potent, selective and orally bioavailable FLT3/CDK4 dual inhibitor with potential antitumor activity.

AMG 925 (FLX925; AMG925) Chemical Structure CAS No.: 1401033-86-0
Product category: FLT3

This product is for research use only, not for human use. We do not sell to patients.

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1-708-310-1919 sales@invivochem.com

Other Forms of AMG 925 (FLX925; AMG925):

AMG 925 HCl

Official Supplier of:

Top Publications Citing lnvivochem Products

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

Science Adv 2022: 8, eabm9427.

Nature 597, 119–125 (2021)

Cell Stem Cell 2020,26(6):845-861.e12.

Science Trans Med 2023,15(701):eadd7872.

STTT 2023,8(1):91.

Cell Reports 2023,42(4):112313

Science Trans Med 2023, 15: eadd7872.

Cancer Cell 2021,39(4):529-547.e7.

Cancer Discov 2022,12(4):1106-1127.

Immunity 2023,56(3):620-634.e11.

J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

PNAS Nexus 2022,1(3):pgac063.

ACS Nano 2023,17(10):9110-9125.

Biomaterial 2023 Sep16:302:122333.

Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

NMR

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Biological Data

Product Description

AMG 925 (also called FLX-925; AMG-925) is a novel, potent, selective and orally bioavailable FLT3/CDK4 dual inhibitor with potential antitumor activity. Its IC50 values for FLT3/CDK4 inhibition are 1 nM and 3 nM, respectively. By inhibiting P-FLT3 and P-STAT5 and causing apoptosis, AMG 925 inhibits cell growth with IC50 values of 19 nM and 18 nM, respectively, and demonstrates excellent anti-proliferative activity in vitro. AMG 925 treatment inhibits P-STAT5 and P-RB as well as cell growth in both the systemic MOLM13-Luc xenograft tumor model and the subcutaneous MOLM13 xenograft tumor model, demonstrating its high in vivo antitumor efficacy in mice bearing AML tumors.

Biological Activity I Assay Protocols (From Reference)

Targets

FLT3 (IC50 = 2 nM); CDK4 (IC50 = 3 nM); CDK6 (IC50 = 8 nM); CDK2 (IC50 = 375 nM); CDK1 (IC50 = 1.9 μM)

ln Vitro

AMG 925 also has IC50s of 8±2 nM, 375±150 nM, and 1.90±0.51 μM for CDK6, CDK2, and CDK1 inhibition in kinase tests, respectively. Based on KinomScan's analysis of 442 different kinases, AMG 925 has a fair overall kinase selectivity. By comparing AMG 925's growth-inhibiting activity in RB-positive (RB⁺) and RB-negative (RB^-) non-acute myeloid leukemia (AML) cancer cell lines, its cellular selectivity—the ratio of on-target to off-target activity—is nearly 50 times higher. AMG 925 suppresses the growth of AML cell lines Mv4-11 (FLT3-ITD; IC50=18 μM) and MOLM13 (FLT3-ITD; IC50=19 μM) with significant potency.[1]

ln Vivo

AMG 925 at doses of 12.5, 25, or 37.5 mg/kg is given orally to MOLM13 tumor-bearing mice twice a day, six hours different. After that, tumors are taken 3, 9, 12, and 24 hours following the initial dosage, and P-STAT5 and P-RB levels are measured. After 6 and 12 hours, respectively, at a dose of 37.5 mg/kg of AMG 925, the maximum inhibition of P-STAT5 and P-RB is produced. It is noteworthy that P-STAT5 shows an interesting rebound after 24 hours, which could be the consequence of compensatory feedback. AMG 925 plasma concentrations were found to be correlated with the pharmacodynamic responses of P-STAT5 and P-RB inhibition. AMG 925 reduces the growth of AML xenograft tumors by 96% to 99% without causing appreciable weight loss. The pharmacodynamic markers for the inhibition of FLT3 and CDK4, retinoblastoma protein (RB) phosphorylation and STAT5, respectively, are correlated with the antitumor activity of AMG 925. Furthermore, it has been discovered that AMG 925 inhibits FLT3 mutants (like D835Y) that are resistant to the FLT3 inhibitors that are currently on the market (like AC220 and Sorafenib)[1].

Enzyme Assay

Cell Assay

MOLM13 and Mv4-11 are employed. By transfecting MOLM13 cells with the pLV218G luciferin/lentivector, which expresses luciferase under the murine EF1α promoter, MOLM13-Luc cells are created. By passing the cells through growth media containing increasing concentrations of sorafenib (1–1 nM), sorafenib-resistant MOLM13 (MOLM13sr) and Mv4-11 (Mv4-11sr) can be isolated. A DNA synthesis assay is used to quantify cell growth. In a 96-well Cytostar T plate, 5×10³ cells/well are seeded with a total volume of 160 μL. Test compounds (such as AMG 925; 0.03 and 0.3μM) are added to each well of the plate in increments of 20 μL/0.1 μCi after being serially diluted into each well (20 μL/well). After an additional 72 hours of incubation, isotope incorporation is measured with a β plate counter. The Vybrant Apoptosis Assay Kit is used to test for apoptosis. In summary, 5×10⁵ cells per well of a 6-well plate are seeded, and compounds (such as AMG 925; 0.003, 0.01, 0.03, 0.1, 0.3, and 1 μM) are applied for a full day. After staining the cells using the kit's included reagents, the cells are examined using flow cytometry. The resolution of living, apoptotic, and dead cells—which are quantified using the Flowjo software—is displayed in the Sytox Green fluorescence versus allophycocyanin fluorescence dot plot. After subjecting the cells to AMG 925 treatment for a full day, the CycleTest Kit is used to analyze the cell cycle. The cells are treated with AMG 925 for 24 hours, and then the CycleTest Kit is used to analyze the cell cycle. Using the ModFit software, 10,000 events are collected, and the percentages of cells in each cycle phase are computed[1].

Animal Protocol

Mice: NCR-Foxn1^nu (CrTac:NCR) nude mice are employed. On the flank of NCR nude mice, 2×10⁶ cells are inoculated, and they are left to grow for 13 days. AMG 925 is then given orally to mice twice a day, six hours apart, at doses of 12.5, 25, 37.5, and 50 mg/kg for ten days in a row[1].

References

[1]. Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia. Mol Cancer Ther. 2014 Apr;13(4):880-9.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C26H29N7O2
Molecular Weight	471.55
Exact Mass	471.24
Elemental Analysis	C, 66.22; H, 6.20; N, 20.79; O, 6.79
CAS #	1401033-86-0
Related CAS #	AMG 925 HCl;1401034-19-2
Appearance	white solid powder
SMILES	CC1CCC(CC1)N2C3=C(C=CN=C3)C4=CN=C(N=C42)NC5=NC6=C(CN(CC6)C(=O)CO)C=C5
InChi Key	BBUVDDPUURMFOX-UHFFFAOYSA-N
InChi Code	InChI=1S/C26H29N7O2/c1-16-2-5-18(6-3-16)33-22-13-27-10-8-19(22)20-12-28-26(31-25(20)33)30-23-7-4-17-14-32(24(35)15-34)11-9-21(17)29-23/h4,7-8,10,12-13,16,18,34H,2-3,5-6,9,11,14-15H2,1H3,(H,28,29,30,31)
Chemical Name	2-hydroxy-1-[2-[[8-(4-methylcyclohexyl)-4,6,8,11-tetrazatricyclo[7.4.0.02,7]trideca-1(9),2,4,6,10,12-hexaen-5-yl]amino]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]ethanone
Synonyms	FLX 925; AMG925; FLX925; FLX-925; AMG-925; AMG 925
HS Tariff Code	2934.99.9001
Storage	Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

Solubility (In Vitro)

DMSO: ~10 mM

Water: <1 mg/mL

Ethanol: <1 mg/mL

Solubility (In Vivo)

2% hydroxypropyl methylcellulose+1% Tween 80: 30mg/mL

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.1207 mL	10.6033 mL	21.2067 mL
	5 mM	0.4241 mL	2.1207 mL	4.2413 mL
	10 mM	0.2121 mL	1.0603 mL	2.1207 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

Calculator

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
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Click the “Calculate” button
The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
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Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

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Reconstitution Calculator allows you to calculate the volume of solvent required to reconstitute your vial.

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The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

Dosage mg/kg

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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Calculation results

Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O，mix and clarify.

Note： (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.

Biological Data

Activity of AMG 925 in subcutaneous MOLM13 xenograft tumor model.Mol Cancer Ther. 2014 Apr;13(4):880-9.
Activity of AMG 925 in systemic MOLM13-Luc xenograft tumor model. Mol Cancer Ther. 2014 Apr;13(4):880-9.
Activity of AMG 925 in Colo205 xenograft tumor model. Mol Cancer Ther. 2014 Apr;13(4):880-9.