TAK-733

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TAK-733

本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。

CAS NO:	1035555-63-5
规格:	≥98%

包装与价格：

包装	价格(元)
5mg	电议
25mg	电议
50mg	电议
100mg	电议
250mg	电议
500mg	电议

产品介绍

理化性质和储存条件

Molecular Weight (MW)	504.23
Formula	C17H15F2IN4O4
CAS No.	1035555-63-5
Storage	-20℃ for 3 years in powder form
Storage	-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: 101 mg/mL (200.3 mM)
	Water: <1 mg/mL
	Ethanol: <1 mg/mL
SMILES	O=C1C(C(NC2=CC=C(I)C=C2F)=C(F)C(N3C)=O)=C3N=CN1C[C@@H](O)CO
Synonyms	TAK 733; TAK733; TAK-733 Chemical Name: (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione InChi Key: RCLQNICOARASSR-SECBINFHSA-N InChi Code: InChI=1S/C17H15F2IN4O4/c1-23-15-12(16(27)24(7-21-15)5-9(26)6-25)14(13(19)17(23)28)22-11-3-2-8(20)4-10(11)18/h2-4,7,9,22,25-26H,5-6H2,1H3/t9-/m1/s1 SMILES Code: O=C1C(C(NC2=CC=C(I)C=C2F)=C(F)C(N3C)=O)=C3N=CN1C[C@@H](O)CO

实验参考方法

In Vitro	In vitro activity: TAK-733 is a novel potent, selective and orally bioavailable allosteric inhibitor of MEK with IC50 of 3.2 nM for MEK1, it is inactive to Abl1, AKT3, c-RAF, CamK1, CDK2, c-Met, etc. TAK-733 has potential antineoplastic activity and has been advanced to Phase I clinical studies for cancer treatment. It selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. TAK-733 has been reported to broadly inhibit tumor activity in mouse xenograft models of human cancer (melanoma, colorectal, NSCLC, pancreatic and breast cancer). TA Kinase Assay: K-733 is highly potent and selective MEK allosteric site inhibitor with IC50 of 3.2 nM. TAK-733 shows potent enzymatic and cell activity with an EC50 of 1.9 nM against ERK phosphorylation in cells. Cell Assay: TAK-733 showed broad activity in most melanoma cell lines with relative resistance observed at IC50> 0.1 μmol/L in vitro. Moreover, Cell lines with a BRAF or KRAS mutation were associated with sensitivity to TAK-733 with an IC50 value of < 0.5μM.
In Vivo	TAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including models of melanoma, colorectal, NSCLC, pancreatic and breast cancer. TAK-733 is well tolerated with pharmacokinetics and pharmacodynamics that support once-daily oral dosing in humans. TAK-733 shows maximally efficacious doses at once daily orally doses of 10 mg/kg.
Animal model	Human solid tumor xenograft models including NSCLC (NCI H23 [KRAS and LKB1 mutations]), CRC (SW620 [KRAS, APC, p53 mutations]) Pancreatic cancer (Panc 1 and Capan 1 [KRAS mutations] and BxPC-3 [No MAPK mutations]) models in immunocompromised mice.
Formulation & Dosage	Dissolved in saline; 10 mg/kg; Oral gavage
References	Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9.

生物活性

(A) Tumor growth inhibition index of 11 PDTX tumor models administered with TAK-733 (10 mg/kg) for 30 days. (B-E) Representative tumor growth inhibition curves of four melanoma PDTX models administered with vehicle or TAK-733 (10 mg/kg) for the indicated study days. Mol Cancer Ther. 2015 Feb;14(2):317-25.

Pharmacokinetic and pharmacodynamic effects of TAK-733 in A375 tumor-bearing mice following oral administration of (A) 1 mg/kg or (B) 10 mg/kg dose. A375 tumor cells were implanted subcutaneously in the flank of nu/nu mice (3/time point). Administration was initiated when all mice had tumors ranging in size from 300 to 500 mm3 (Day 10). TAK-733 was given as a single oral dose. Mol Cancer Ther. 2015 Feb;14(2):317-25.

Effects of TAK-733 on growth of A375 melanoma tumor xenografts in athymic nude mice. A375 melanoma cells were implanted subcutaneously in the flank of nu/nu mice (5/group). Administration was initiated 10 days after the tumor implant, when all mice had tumors ranging in size from 80 to 225 mm3 (Day 10). TAK-733 was given orally daily for 14 days (QD 1-14) or 3 days per week for 2 cycles (M, TH, SAT ×2). Mol Cancer Ther. 2015 Feb;14(2):317-25.

Tumor regrowth kinetics for PDTX model MB1374 administered with vehicle or TAK-733 (10 mg/kg). Inset, original tumor growth inhibition study for 30 days. Red lines indicate TAK-733 administration times, black lines indicate cessation of TAK-733 for tumor regrowth periods. Mol Cancer Ther. 2015 Feb;14(2):317-25.

Antiproliferative effects of TAK-733 against a panel of human cutaneous melanoma cell lines. Cell lines were treated with increasing doses of TAK-733 for 72 hours and proliferation was assessed using the SRB assay. IC50 values are depicted. BRAF and NRAS mutational status in depicted in the table below. Mol Cancer Ther. 2015 Feb;14(2):317-25.

Immunoblot analysis of downstream effectors upon administration of TAK-733. A375 and RPMI 7951 cell lines were serum starved overnight and then administered TAK-733 for 1 hr. Cells were then challenged with 10% FBS for 30 mins, harvested and immunoblotted with the indicated antibodies. Mol Cancer Ther. 2015 Feb;14(2):317-25.