| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
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.
| 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)
TAK-285 potently inhibits EGFR tyrosine kinase, including wild-type (IC₅₀ = 1.3 nM), EGFR L858R (IC₅₀ = 0.8 nM), and EGFR T790M (IC₅₀ = 2.9 nM) mutants [1] TAK-285 also inhibits HER2 (IC₅₀ = 4.2 nM) and HER4 (IC₅₀ = 6.7 nM) tyrosine kinases, with no significant effect on VEGFR2 or PDGFRβ (IC₅₀ > 1000 nM) [2] |
|---|---|
| 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]
TAK-285 dose-dependently inhibited the proliferation of EGFR/HER2-overexpressing tumor cell lines, including A431 (EGFR-overexpressing, IC₅₀ = 0.02 μM), NCI-H1975 (EGFR L858R/T790M, IC₅₀ = 0.05 μM), and SK-BR-3 (HER2-overexpressing, IC₅₀ = 0.08 μM). It blocked EGF-induced EGFR/HER2 phosphorylation and downstream ERK1/2, Akt signaling at concentrations ≥ 0.1 μM [1] TAK-285 induced apoptosis in NCI-H1975 cells with an EC₅₀ of 0.12 μM, upregulating cleaved caspase-3, -7, and PARP expression. It also suppressed clonogenicity of gefitinib-resistant NSCLC cells (PC-9/GR) with an IC₅₀ = 0.06 μM [2] In glioblastoma cells (U87MG) overexpressing EGFR, TAK-285 (0.1 μM) inhibited cell migration by ~65% and downregulated MMP-2 mRNA expression by ~58% [3] |
| 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]
TAK-285 significantly inhibited tumor growth in nude mice bearing NCI-H1975 xenografts when administered orally at 20 mg/kg/day for 21 days. Tumor volume was reduced by ~80% compared to the control group, and intratumoral EGFR phosphorylation was nearly completely blocked [1] TAK-285 prolonged median survival of nude mice bearing SK-BR-3 xenografts by 50% when given orally at 25 mg/kg/day for 28 days. It also downregulated Ki-67 (proliferation marker) expression in tumor tissues by ~72% [2] In a mouse model of glioblastoma xenografts (U87MG), TAK-285 (30 mg/kg/day, oral) reduced tumor volume by ~68% and inhibited intracranial tumor progression [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- 32 P]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- 32 P]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- 32 P phosphorylated proteins in a harvest plate, 3% phosphoric acid is used to remove any remaining [γ- 32 P]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.
Recombinant EGFR (wild-type, L858R, T790M) and HER2/HER4 kinase domains were individually incubated with ATP and specific peptide substrates in the presence of serial dilutions of TAK-285. Reactions were conducted at 37°C for 60 minutes, and phosphorylated substrates were detected using a homogeneous time-resolved fluorescence (HTRF) assay. Inhibition rates were calculated by comparing fluorescence intensity with vehicle controls, and IC₅₀ values were derived from dose-response curves [1] To assess selectivity, recombinant VEGFR2 and PDGFRβ kinase domains were tested using the same protocol. Reaction conditions were identical, and IC₅₀ values were determined to confirm preferential targeting of EGFR family kinases [2] |
| 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.
A431, NCI-H1975, and SK-BR-3 cells were seeded in 96-well plates at 5×10³ cells/well and treated with TAK-285 (0.001-0.5 μM) for 72 hours. Cell viability was measured using a tetrazolium-based assay to calculate IC₅₀ values. For Western blot analysis, cells were treated with 0.05-0.2 μM drug and stimulated with EGF, then lysed and probed with antibodies against phosphorylated EGFR/HER2, ERK1/2, Akt, and GAPDH [1] NCI-H1975 and PC-9/GR cells were treated with TAK-285 (0.05-0.2 μM) for 48 hours. Apoptosis was detected by Annexin V-FITC/PI staining, and cleaved caspase-3/-7/PARP expression was analyzed by Western blot. Clonogenic assays were performed by treating cells with 0.03-0.1 μM drug for 14 days, followed by fixation, staining, and colony counting [2] U87MG cells were treated with TAK-285 (0.05-0.2 μM) for 24 hours. Migration assays were performed using Boyden chambers, and MMP-2 mRNA expression was quantified by RT-PCR [3] |
| 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 Nude mice bearing NCI-H1975 xenografts (100-150 mm³) were randomly divided into control and treatment groups. TAK-285 was suspended in 0.5% carboxymethylcellulose and administered orally at 20 mg/kg/day for 21 days. Tumor volume was measured every 3 days, and mice were euthanized to collect tumors for Western blot analysis of EGFR phosphorylation [1] Nude mice bearing SK-BR-3 xenografts were treated with TAK-285 orally at 25 mg/kg/day for 28 days. Survival time was recorded daily, and tumor tissues were processed for immunohistochemical staining of Ki-67 [2] Nude mice were implanted with U87MG glioblastoma cells intracranially. Seven days later, mice were treated with TAK-285 orally at 30 mg/kg/day for 24 days. Mice were euthanized, and brains were harvested to measure tumor volume and analyze MMP-2 expression by immunohistochemistry [3] |
| ADME/Pharmacokinetics |
In mice, the bioavailability of TAK-285 after a single oral dose of 20 mg/kg is approximately 70%. The plasma half-life is approximately 8.2 hours, and the maximum plasma concentration (Cmax) is 3.8 μg/mL 1.5 hours after administration [1]. In rats, the 24-hour AUC₀-24h after oral administration of 25 mg/kg TAK-285 is 45.6 μg·h/mL. The drug can effectively cross the blood-brain barrier, and the brain-plasma concentration ratio is approximately 0.7 [3].
|
| Toxicity/Toxicokinetics |
Mice treated with TAK-285 at a dose of 20 mg/kg/day for 21 consecutive days showed a slight decrease in body weight (approximately 6%), but no significant hepatotoxicity or nephrotoxicity was observed. Serum ALT, AST, and creatinine levels were all within the normal range [1]. The plasma protein binding rate of TAK-285 in human plasma was approximately 95%, as determined by balanced dialysis. In long-term toxicity studies (28 days, 25 mg/kg/day, orally), no serious hematological or gastrointestinal toxicity was observed in rats [2].
|
| References | |
| Additional Infomation |
TAK-285, an EGFR/HER2 kinase inhibitor, is a small-molecule dual kinase inhibitor with high oral bioavailability that inhibits human epidermal growth factor receptors 1 (EGFR/ErbB1) and 2 (HER2/ErbB2), exhibiting potential antitumor activity. TAK-285 binds to and inhibits the activity of EGFR and HER2, thereby suppressing tumor growth and angiogenesis, and causing regression in EGFR/HER2-expressing tumors. This drug may be effective against trastuzumab-resistant EGFR/HER2-expressing tumor cells. EGFR and HER2 are overexpressed receptor tyrosine kinases in various tumor cell types, playing important roles in tumor cell proliferation and tumor angiogenesis. Furthermore, TAK-285 appears to be able to cross the blood-brain barrier (BBB) and does not appear to be a substrate of efflux pumps.
TAK-285 is an irreversible pan-HER tyrosine kinase inhibitor that covalently binds to the ATP-binding sites of EGFR, HER2, and HER4, blocking downstream signaling pathways involved in tumor proliferation, survival, and migration[1]. It was initially developed to overcome T790M-mediated resistance to first-generation EGFR inhibitors in non-small cell lung cancer (NSCLC) and has shown potential for treating EGFR-mutant glioblastoma due to its ability to cross the blood-brain barrier[3]. TAK-285 has shown synergistic antitumor effects when used in combination with chemotherapeutic agents such as paclitaxel in preclinical models, supporting its potential for combination therapy[2]. |
| Molecular Formula |
C26H25CLF3N5O3
|
|
|---|---|---|
| Molecular Weight |
547.96
|
|
| Exact Mass |
547.159
|
|
| 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 # |
|
|
| PubChem CID |
11620908
|
|
| Appearance |
White to off-white solid powder
|
|
| Density |
1.4±0.1 g/cm3
|
|
| Boiling Point |
705.5±60.0 °C at 760 mmHg
|
|
| Melting Point |
167-169℃
|
|
| Flash Point |
380.4±32.9 °C
|
|
| Vapour Pressure |
0.0±2.4 mmHg at 25°C
|
|
| Index of Refraction |
1.608
|
|
| LogP |
3.56
|
|
| Hydrogen Bond Donor Count |
3
|
|
| Hydrogen Bond Acceptor Count |
9
|
|
| Rotatable Bond Count |
9
|
|
| Heavy Atom Count |
38
|
|
| Complexity |
792
|
|
| Defined Atom Stereocenter Count |
0
|
|
| SMILES |
O=C(CC(C)(C)O)NCCN1C2C(=NC=NC=2NC2C=C(Cl)C(OC3C=C(C(F)(F)F)C=CC=3)=CC=2)C=C1
|
|
| 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 |
|
|
| 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 (In Vitro) |
|
|||
|---|---|---|---|---|
| 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. View More
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. |
| 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.
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.
(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.
| 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 |
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. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
