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Bafetinib Sale

(Synonyms: 巴氟替尼; INNO-406; NS-187) 目录号 : GC35462

A Bcr-Abl inhibitor

Bafetinib Chemical Structure

Cas No.:859212-16-1

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥665.00
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5mg
¥525.00
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10mg
¥910.00
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50mg
¥1,750.00
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100mg
¥3,150.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Kinase experiment [1]:

Kinase assays

Bcr-Abl kinase assays were performed in 25 μL of reaction mixture containing 250 μM peptide substrate, 740 Bq/μL [γ-33P]ATP, and 20 μM cold adenosine triphosphate (ATP) by using the SignaTECT protein tyrosine kinase assay system. Each Bcr-Abl kinase was used at a concentration of 10 nM. Kinase assays for Abl, Src, and Lyn were carried out with an enzyme-linked immunosorbent assay (ELISA) kit from Carna Biosciences.

Cell experiment [1]:

Cell lines

K562, BaF3/wt and KU812 cell lines

Preparation method

The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

0-10 μM for 3 days

Applications

Bafetinib could suppress the growth of the Bcr-Abl–positive cell lines K562, KU812, and BaF3/wt.

Animal experiment [1]:

Animal models

Bcr-Abl–positive KU812 mouse model

Dosage form

0.2 mg/kg/d and 20 mg/kg/d orally twice a day for 26 consecutive days

Application

Bafetinib suppressed the growth of Bcr-Abl–bearing tumors (KU812) and markedly extends the survival of mice bearing such tumors.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Kimura S, Naito H, Segawa H, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood, 2005, 106(12): 3948-3954.

产品描述

Bcr-Abl, a fusion protein with deregulated tyrosine kinase activity, is highly expressed in chronic myelogenous leukemia (CML). Bafetinib is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib , with modifications added to improve binding and potency against Bcr-Abl kinase (IC50 = 5.8 nM).1 It is 25- to 55-fold more potent than imatinib in vitro and ≥10-fold more potent in vivo.1 Bafetinib inhibits 12 out of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not the T315I mutation and also targets the Src family kinase Lyn (IC50 = 19 nM), which has been associated with resistance to imatinib in CML.1

1.Kimura, S., Naito, H., Segawa, H., et al.NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemiaBlood106(12)3948-3954(2005)

Chemical Properties

Cas No. 859212-16-1 SDF
别名 巴氟替尼; INNO-406; NS-187
化学名 (S)-N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)benzamide
Canonical SMILES O=C(NC1=CC=C(C)C(NC2=NC=CC(C3=CN=CN=C3)=N2)=C1)C4=CC=C(CN5C[C@@H](N(C)C)CC5)C(C(F)(F)F)=C4
分子式 C30H31F3N8O 分子量 576.62
溶解度 DMSO: ≥ 42 mg/mL (72.84 mM) 储存条件 Store at -20°C
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储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 1.7342 mL 8.6712 mL 17.3424 mL
5 mM 0.3468 mL 1.7342 mL 3.4685 mL
10 mM 0.1734 mL 0.8671 mL 1.7342 mL
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Research Update

Bafetinib Suppresses the Transcription of PD-L1 Through c-Myc in Lung Cancer

Front Pharmacol 2022 Jun 2;13:897747.PMID:35721177DOI:10.3389/fphar.2022.897747.

Given the limitations of the existing antibody-based therapies, including immune-related adverse events, poor response rates, and intravenous route of dosing, small molecules inhibitors targeting PD-L1 are highly desirable. By cell-based screening, we found that tyrosine kinase inhibitor Bafetinib dramatically suppresses PD-L1 protein expression in a dose-dependent manner. In parallel, cell membrane PD-L1 is also reduced by Bafetinib. We confirm that Bafetinib doesn't affect the protein half-life of PD-L1 but significantly inhibits the transcription of PD-L1. Among the transcription factors that regulate PD-L1 expression, c-Myc is downregulated by Bafetinib. Bafetinib caused PD-L1 inhibition is abolished when c-Myc is knocked-down. Further, we identified that Bafetinib reduced c-Myc expression because of transcription inhibition. By using the CT26 tumor model, we further confirm that Bafetinib suppressed PD-L1 expression in vivo. In conclusion, our study shows that Bafetinib inhibits the transcription of PD-L1 through transcription factor c-Myc, suggesting that Bafetinib might be a small molecule drug targeting PD-L1.

Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia

Curr Opin Investig Drugs 2010 Dec;11(12):1450-65.PMID:21154127doi

Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, Bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, Bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinib inhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of Bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that Bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, Bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors.

Bafetinib inhibits functional responses of human eosinophils in vitro

Eur J Pharmacol 2013 Sep 5;715(1-3):172-80.PMID:23747655DOI:10.1016/j.ejphar.2013.05.025.

Eosinophils play a prominent role in the process of allergic inflammation. Non-receptor associated Lyn tyrosine kinases generate key initial signals in eosinophils. Bafetinib, a specific Abl/Lyn tyrosine kinase inhibitor has shown a potent antiproliferative activity in leukemic cells, but its effects on eosinophils have not been reported. Therefore, we studied the effects of Bafetinib on functional and mechanistic responses of isolated human eosinophils. Bafetinib was more potent than non-specific tyrosin kinase comparators genistein and tyrphostin inhibiting superoxide anion triggered by N-formyl-Met-Leu-Phe (fMLF; 100 nM) (-log IC50=7.25 ± 0.04 M; 6.1 ± 0.04 M; and 6.55 ± 0.03 M, respectively). Bafetinib, genistein and tyrphostin did not modify the [Ca(2+)]i responses to fMLF. Bafetinib inhibited the release of EPO induced by fMLF with higher potency than genistein and tyrphostin (-log IC50=7.24 ± 0.09 M; 5.36 ± 0.28 M; and 5.37 ± 0.19 M, respectively), and nearly suppressed LTC4, ECP and chemotaxis. Bafetinib, genistein and tyrphostin did not change constitutive apoptosis. However Bafetinib inhibited the ability of granulocyte-monocyte colony-stimulating factor to prevent apoptosis. The activation of Lyn tyrosine kinase, p-ERK1/2 and p-38 induced by fMLF was suppressed by Bafetinib and attenuated by genistein and tyrphostin. In conclusion, Bafetinib inhibits oxidative burst and generation of inflammatory mediators, and reverses the eosinophil survival. Therefore, future anti-allergic therapies based on Bafetinib, could help to suppress excessive inflammatory response of eosinophils at inflammatory sites.

Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy

J Hematol Oncol 2018 Jun 20;11(1):84.PMID:29925402DOI:10.1186/s13045-018-0624-2.

Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action had been elucidated to rationally develop those second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on Bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.

Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

Sci Rep 2016 May 9;6:25694.PMID:27157787DOI:10.1038/srep25694.

ATP-Binding Cassette transporters are involved in the efflux of xenobiotic compounds and are responsible for decreasing drug accumulation in multidrug resistant (MDR) cells. Discovered by structure-based virtual screening algorithms, Bafetinib, a Bcr-Abl/Lyn tyrosine kinase inhibitor, was found to have inhibitory effects on both ABCB1- and ABCG2-mediated MDR in this in-vitro investigation. Bafetinib significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [(3)H]-paclitaxel in ABCB1 overexpressing cells; mitoxantrone and [(3)H]-mitoxantrone in ABCG2 overexpressing cells, respectively. Bafetinib stimulated ABCB1 ATPase activities while inhibited ABCG2 ATPase activities. There were no significant changes in the expression level or the subcellular distribution of ABCB1 and ABCG2 in the cells exposed to 3 μM of Bafetinib. Overall, our study indicated that Bafetinib reversed ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings might be useful in developing combination therapy for MDR cancer treatment.