TAK-285

Alias: TAK 285; TAK-285; TAK285

Cat No.:V0555 Purity: ≥98%

COA Product Data Instructions for use SDS

TAK-285 (TAK285), currently being investigated by Takeda company, is a dual HER2/EGFR(HER1) inhibitor with potential antitumor activity.

TAK-285 Chemical Structure CAS No.: 871026-44-7
Product category: EGFR

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

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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

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Clinical Trial Information
Biological Data

Product Description

TAK-285 (TAK285), currently being investigated by Takeda company, is a dual HER2/EGFR(HER1) inhibitor with potential antitumor activity. Its IC50 values for HER2/1 inhibition are 17 nM and 23 nM. More than ten times more selective for HER1/2 than HER4, it is less effective against MEK1/5, Aurora B, Lck, c-Met, CSK, and other substances.

Biological Activity I Assay Protocols (From Reference)

Targets

HER2 (IC50 = 17 nM); EGFR/HER1 (IC50 = 23 nM); HER4 (IC50 = 260 nM); MEK1 (IC50 = 1.1 μM); Aurora B (IC50 = 1.7 μM)

ln Vitro

Among the 34 kinases tested, TAK-285 only significantly inhibits HER4 with IC50 of 260 nM, slightly inhibits MEK1, MEK5, c-Met, Aurora B, Lck, CSK, and Lyn B with IC50 of 1.1 μM, 5.7 μM, 4.2 μM, 1.7 μM, 2.4 μM, 4.7 μM, and 5.2 μM, respectively, and displays no activity against other kinases with IC50 of >10 μM. TAK-285 shows significant growth inhibitory activity against BT-474 cells (HER2-overexpressing human breast cancer cell line) with GI50 of 17 nM.[1] TAK-285 exhibits comparable in vitro potency against EGFR and HER2 in comparison to SYR127063, a potent HER2 inhibitor. The inhibitory activity (IC50) of TAK-285 is not significantly affected by the mutations and shortened boundaries used for HER2-KD and EGFR-KD structure determination when compared to the full cytoplasmic domains of the wild-type proteins. TAK-285 exhibits a comparable binding mode to lapatinib in the active site when it comes to binding to the inactive conformation of EGFR.[2]

ln Vivo

TAK-285 has an oral bioavailability of 72.2% in mice and 97.7% in rats at a dose of 50 mg/kg. In the HER2-overexpressing BT-474 tumor xenograft mouse model, oral TAK-285 at 100 mg/kg twice daily for 14 days significantly reduces tumor growth without changing body weight, and the tumor/control (T/C) ratio is 29%. TAK-285, like the BT-474 model, shows dose-dependent inhibition of tumor growth of 4-1ST (HER2-overexpressing human gastric cancer tumor) xenografts in mice, with T/C of 44% and 11% at doses of 50 mg/kg and 100 mg/kg, twice daily, respectively, without causing a significant reduction in the mice's body weight. In addition, TAK-285 treatment results in tumor regression with T/C of -12% and -16% at doses of 25 mg/kg and 50 mg/kg, respectively, and dose-dependent growth inhibition of 4-1ST tumors in rats with T/C of 38% and 14% at doses of 6.25 mg/kg and 12.5 mg/kg. [1] Following oral administration of TAK-285, rats' brains contain a sizable amount of the drug in an unbound, pharmacologically active form (roughly 20% of its free plasma level), suggesting that TAK-285 may be used to treat CNS cancers and their metastases.[3]

Enzyme Assay

The cytoplasmic domains of human HER2 (amino acids 676–1255) and human EGFR (amino acids 669–1210) are expressed via a baculovirus expression system as N-terminal peptide (DYKDDDD)-tagged protein. Anti-FLAG M2 affinity gel is used to separate the expressed EGFR and HER2 kinases. Radiolabeled [γ-³²P]ATP is used in 96-well plates for the EGFR and HER2 kinase assays. Each purified cytoplasmic domain (0.25 μg/mL EGFR or HER2) in a total volume of 50 μL, 50 μM ATP, 5 ug/mL poly(Glu)-Tyr (4:1), and 0.9 uCi of [γ-³²P]ATP per reaction are added to the 50 μL of Tris-HCl (pH 7.5), 0.01% Tween 20, and 2 mM DTT. The enzyme is incubated with increasing concentrations of TAK-285 for five minutes at room temperature before the reaction is measured to determine the IC50 value for enzyme inhibition. ATP is added to start the kinase reactions. The reactions are halted by adding 10% (final concentration) trichloroacetic acid after 10 minutes at room temperature. After using a cell harvester to filter the γ-³²P phosphorylated proteins in a harvest plate, 3% phosphoric acid is used to remove any remaining [γ-³²P]ATP. MicroScint0 (25 μL) is added to the plates after they have dried. A TopCount scintillation counter measures radioactivity. The nonlinear regression analysis of the percent inhibitions is used to compute the IC50 values.

Cell Assay

For five days, the cells are continuously treated with TAK-285 at different concentrations. A particle analyzer is used to count the number of live cells.

Animal Protocol

Female BALB/c nu/nu mice bearing BT-474 or 4-1ST xenografts, and female nude rats (F344/N Jcl-rnu) bearing 4-1ST xenografts
~100 mg/kg/day
Orally twice daily

References

[1]. J Med Chem . 2011 Dec 8;54(23):8030-50.

[2]. J Biol Chem . 2011 May 27;286(21):18756-65.

[3]. Brain Res Bull . 2012 Mar 10;87(4-5):413-9.

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

Physicochemical Properties

Molecular Formula

C26H25CLF3N5O3

Molecular Weight

547.96

Exact Mass

547.16

Elemental Analysis

C, 56.99; H, 4.60; Cl, 6.47; F, 10.40; N, 12.78; O, 8.76

CAS #

871026-44-7

Related CAS #

871026-44-7

Appearance

White to off-white solid powder

SMILES

CC(C)(CC(=O)NCCN1C=CC2=C1C(=NC=N2)NC3=CC(=C(C=C3)OC4=CC=CC(=C4)C(F)(F)F)Cl)O

InChi Key

ZYQXEVJIFYIBHZ-UHFFFAOYSA-N

InChi Code

InChI=1S/C26H25ClF3N5O3/c1-25(2,37)14-22(36)31-9-11-35-10-8-20-23(35)24(33-15-32-20)34-17-6-7-21(19(27)13-17)38-18-5-3-4-16(12-18)26(28,29)30/h3-8,10,12-13,15,37H,9,11,14H2,1-2H3,(H,31,36)(H,32,33,34)

Chemical Name

N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide

Synonyms

TAK 285; TAK-285; TAK285

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: ~110 mg/mL (~200.7 mM)

Water: <1 mg/mL

Ethanol: ~54 mg/mL (~98.5 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 2.5 mg/mL (4.56 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.8250 mL	9.1248 mL	18.2495 mL
	5 mM	0.3650 mL	1.8250 mL	3.6499 mL
	10 mM	0.1825 mL	0.9125 mL	1.8250 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

Mass

Concentration

Volume

Molecular Weight*

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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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Calculate the Volume of solution required to dissolve a compound of known mass to a desired concentration
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See Example

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
Enter 10 in the Concentration box and choose the correct unit (mM)
Enter 5 in the Volume box and choose the correct unit (mL)
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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Concentration (End)

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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)
Enter 25 into the Concentration (End) box and select the correct unit (mM)
Enter 25 into the Volume (End) box and choose the correct unit (mL)
Click the “Calculate” button
The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

Total molecular weight

g/mol

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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
Instructions to calculate molar mass (molecular weight) of a chemical compound:

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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.

Enter the mass of the reagent and the desired reconstitution concentration as well as the correct units
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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

Average weight of animals g

Dosing volume per animal μL

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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.

Clinical Trial Information

NCT Number	Recruitment	interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT00535522	Completed	Drug: TAK-285 Dose Escalation Cohorts Drug: TAK-285 Recommended Phase 2 Dosing Cohort	Cancer	Millennium Pharmaceuticals, Inc.	August 2007	Phase 1

Biological Data

Overall structure of HER2·SYR127063 and EGFR·TAK-285.J Biol Chem.2011 May 27;286(21):18756-65.
Origins of α-helix C conformational flexibility in HER2.J Biol Chem.2011 May 27;286(21):18756-65.
HER2 and EGFR mechanism of inhibition.J Biol Chem.2011 May 27;286(21):18756-65.