ホームページ Protein Tyrosine Kinase EGFR inhibitor - HER2 inhibitor TAK-285 For research use only.

TAK-285

TAK-285 is a novel dual HER2 and EGFR(HER1) inhibitor with IC50 of 17 nM and 23 nM, >10-fold selectivity for HER1/2 than HER4, less potent to MEK1/5, c-Met, Aurora B, Lck, CSK etc. Phase 1.

TAK-285化学構造

CAS No. 871026-44-7

サイズ 価格(税別) 在庫状況
JPY 46800 国内在庫あり
JPY 80000 国内在庫あり

代表番号: 045-509-1970|電子メール：[email protected]
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文献中Selleckの製品使用例（4）

製品安全説明書

現在のバッチを見る： S278401 DMSO] 110 mg/mL] false] Ethanol] 54 mg/mL] false] Water] Insoluble] false 純度： 98.54%
98.54

TAK-285関連製品

シグナル伝達経路

EGFR Signaling Pathways

EGFRシグナル伝達経路

EGFR阻害剤の選択性比較

生物活性

製品説明 TAK-285 is a novel dual HER2 and EGFR(HER1) inhibitor with IC50 of 17 nM and 23 nM, >10-fold selectivity for HER1/2 than HER4, less potent to MEK1/5, c-Met, Aurora B, Lck, CSK etc. Phase 1.
Targets
HER2 [1] EGFR/HER1 [1] HER4 [1] MEK1 [1] Aurora B [1] もっとクリックする
17 nM 23 nM 260 nM 1.1 μM 1.7 μM
In Vitro
In 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] Compared with SYR127063 a potent inhibitor of HER2, TAK-285 displays similar in vitro potency against HER2 and EGFR. Compared with the full cytoplasmic domains of the wild-type proteins, the mutations and shortened boundaries used for structure determination of HER2-KD and EGFR-KD do not significantly change the inhibitory activity (IC50) of TAK-285. TAK-285 binds to the inactive conformation of EGFR, and shows a similar binding mode with lapatinib in the active site. [2]
Kinase Assay HER2 and EGFR kinase assay
The cytoplasmic domain (amino acids 676-1255) of human HER2 and the cytoplasmic domain (amino acids 669-1210) of human EGFR are expressed as N-terminal peptide (DYKDDDD)-tagged protein using a baculovirus expression system. The expressed HER2 kinase and EGFR kinase are purified by anti-FLAG M2 affinity gel. The EGFR and HER2 kinase assays are performed using radiolabeled [γ-32P]ATP in 96-well plates. The kinase reactions are performed in 50 mM Tris-HCl (pH 7.5), 5 mM MnCl2, 0.01% Tween 20, and 2 mM DTT containing 0.9 uCi of [γ-32P]ATP per reaction, 50 μM ATP, 5 ug/mL poly(Glu)-Tyr (4:1), and each purified cytoplasmic domain (0.25 μg/mL EGFR or HER2) in a total volume of 50 μL. To measure the IC50 value for enzyme inhibition, Increasing concentrations of TAK-285 are incubated with the enzyme for 5 minutes prior to the reaction at room temperature. The kinase reactions are initiated by adding ATP. After 10 minutes at room temperature, the reactions are stopped by the addition of 10% (final concentration) trichloroacetic acid. The γ-32P phosphorylated proteins are filtrated in a harvest plate with a cell harvester and washed free of [γ-32P]ATP with 3% phosphoric acid. The plates are dried followed by the addition of 25 μL of MicroScint0. The radioactivity is counted by a TopCount scintillation counter. IC50 values are calculated by nonlinear regression analysis of the percent inhibitions.
細胞実験 細胞株 BT-474
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 5 days
実験の流れ The cells are treated continuously with various concentrations of TAK-285 for 5 days. The live cell numbers are counted with a particle analyzer.
In Vivo
In Vivo The oral bioavailability of TAK-285 is 97.7% in rats and 72.2% in mice at a dose of 50 mg/kg. Oral administration of TAK-285 at 100 mg/kg twice daily for 14 days displays significant antitumor efficacy in the HER2-overexpressing BT-474 tumor xenograft mouse model with tumor/control (T/C) ratio of 29%, without affecting body weight. Similar to the BT-474 model, TAK-285 exhibits dose-dependent tumor growth inhibition 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 significant body weight loss in mice. Furthermore, TAK-285 treatment induces 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, and, particularly noteworthy, tumor regression with T/C of -12% and -16% at doses of 25 mg/kg and 50 mg/kg, respectively. [1] After oral administration of TAK-285, a significant amount of TAK-285 is present in the brain of rats in pharmacologically active, unbound form (approximately 20% of its free plasma level), indicating that TAK-285 has a potential in the therapy of CNS malignancies/metastases. [3]
動物実験 動物モデル 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
投与量 ~100 mg/kg/day
投与経路 Orally twice daily

化学情報

分子量 547.96 化学式

C26H25ClF3N5O3
CAS No. 871026-44-7 SDF Download TAK-285 SDFをダウンロードする
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
保管

In vitro
Batch:

DMSO : 110 mg/mL ( (200.74 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 54 mg/mL

Water : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

mg/kg g μL 匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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