Corynoxine_B_DataSheet_MedChemExpress

Home·Pfizer’s Potential Mega-Blockbuster Breast Cancer Drug 辉瑞口服乳腺癌药物帕博西尼(palbociclib)Pfizer’s PotentialMega-Blockbuster Breast Cancer Drug 辉瑞口服乳腺癌药物帕博西尼(palbociclib)2015年9月5日辉瑞公司的口服乳腺癌药物帕博西尼(palbociclib, Ibrance, 帕博西林)能否成为重磅炸弹产品？帕博西尼(Palbociclib)是近来备受关注的也是辉瑞最重要试验药物之一，2015年2月3日FDA提前批准辉瑞CDK4/6双抑制剂Palbociclib （商品名Ibrance）作为一线药物治疗ER阳性、HER2阴性乳腺癌，比原定4月13日的PDUFA日期提前两个多月。

分析人士预计，palbociclib每年销售额最高可达到30亿-50亿美元之多。

在一项2期临床研究中，使晚期乳腺癌患者的无进展生存期(PFS)平均增加一倍，但对患者总生存期(OS)未显示有统计学意义上的明显改善。

据研究人员2014年4月在圣地亚哥举行的美国癌症研究协会会议上发布的最新数据显示，雌激素受体阳性转移性乳腺癌患者在合并使用Palbociclib与抗雌激素药物来曲唑时，其PFS平均为20.2个月，相比之下，单独使用来曲唑的患者其PFS平均为10.2个月。

辉瑞公司决定在今年第三季度根据乳腺癌试验药物Palbociclib的2期临床试验结果即向美国食品药监局（FDA)申请上市批准，Palbociclib（又名PD-0332991）最早进入人们视野的是在2012年圣安东尼奥乳腺癌会议上（SABCS），一经发布就引起行业广泛关注。

Palbociclib是一种口服的细胞周期素依赖性激酶4、6的抑制药物，主要通过调节细胞周期发挥作用。

Palbociclib主要通过抑制CDK4/6活性来阻止细胞由G1期到S期进而抑制DNA的合成。

Inhibitors, Agonists, Screening Libraries Data SheetBIOLOGICAL ACTIVITY:BFH772 is a potent oral VEGFR2 inhibitor, which is highly effective at targeting VEGFR2 kinase with an IC 50 value of 3 nM.IC50 & Target: IC50: 2.7±0.9 nM (hVEGFR2), 1.5±0.53 μM (mVEGFR2), 1.7±0.36 μM (hVEGFR1), 1.1±0.29 μM (hVEGFR3)[1]In Vitro: BFH772 is highly selective; apart from inhibiting VEGFR2 at 3 nM IC 50, it also targets B–RAF, RET, and TIE–2, albeit with atleast 40–fold lower potency. BFH772 is inactive (IC 50>10 μM; >2 μM for cKIT) against all other tyrosine specific– andserine/threonine–specific protein kinases tested. BFH772 inhibits VEGFR2 with IC 50 of 4.6±0.6 nM in CHO cells. BFH772 inhibits VEGFR2 with IC 50 of 3 nM in HUVEC cells. BFH772 inhibits the ligand induced autophosphorylation of RET, PDGFR, and KIT kinases,with IC 50 values ranging between 30 and 160 nM. BFH772 is selective (IC 50 values >0.5 μM) against the kinases of EGFR, ERBB2,INS–R, and IGF–1R and against the cytoplasmic BCR–ABL kinase. IC 50 of BFH772 (<0.01 nM, n=2) demonstrates that they abrogated VEGF induced proliferation at remarkably low nM concentrations [1].In Vivo: BFH772 at 3 mg/kg orally dosed once per day potently inhibits melanoma growth (by 54–90% for primary tumor and71–96% for metastasis growth) as depicted by treatment to control ratios. Dose–response curves of BFH772 at 0.3, 1, and 3 mg/kg demonstrate that even at the lowest concentrations, this naphthalene–1–carboxamide inhibits VEGF induced tissue weight and TIE–2 levels but only reaches statistical significance at 1 mg/kg and above [1].PROTOCOL (Extracted from published papers and Only for reference)Kinase Assay:[1]In vitro kinase assay is based on a filter binding assay, using the recombinant GST–fused kinase domainsexpressed in baculovirus and purified over glutathione–sepharose, γ–[33P]ATP as the phosphate donor, and poly(Glu:Tyr 4:1) peptide as the acceptor. Each GST–fused kinase is incubated under optimized buffer conditions [20 mM Tris–HCl buffer (pH 7.5), 1–3 mM MnCl 2, 3–10 mM MgCl 2, 3–8 μg/mL poly(Glu:Tyr 4:1), 0.25 mg/mL polyethylene glycol 20000, 8 μM ATP, 10 μM sodium vanadate, 1mM DTT] and 0.2 μCi γ–33P ATP in a total volume of 30 μL in the presence or absence of a test substance for 10 min at ambient temperature. The reaction is stopped by adding 10 mL of 250 mM EDTA. Using a 384–well filter system, half the volume istransferred onto an Immobilon–polyvinylidene difluoride membrane. The membrane is then washed extensively and dried, and scintillation counting is performed. IC 50s for compounds are calculated by linear regression analysis of the percentage inhibition [1].Cell Assay: BFH772 is dissolved in DMSO (10 mM) and stored, and then diluted with appropriate medium before use [1]. [1]DifferentBa/F3 cell lines rendered IL–3 independent by transduction with various constitutively active tyrosine kinases are grown in RPMI 1640 medium containing 10% fetal calf serum. For maintenance of parental Ba/F3 cells, the medium is additionally supplemented with 10 ng/mL interleukin–3 (IL–3). For proliferation assays, Ba/F3 cells are seeded on 96–well plates in triplicates at 10000 cells per well and incubated with various concentrations of compounds for 72 h followed by quantification of viable cells using a resazurin sodium salt dye reduction readout (commercially known as Alamar Blue assay). IC 50s are determined with the XLFit Excel Add–In using a four–parameter dose response model [1].Animal Administration: BFH772 is prepared in PEG200 100% (Mice)[1].Product Name:BFH772Cat. No.:HY-100419CAS No.:890128-81-1Molecular Formula:C 23H 16F 3N 3O 3Molecular Weight:439.39Target:VEGFR Pathway:Protein Tyrosine Kinase/RTK Solubility:DMSO: 7.75 mg/mLBFH772 is dissolved in N–methyl pyrrolidone/polyethylene glycol200 (30:70, v/v) (Rat)[1].[1]Mice[1]Female FVB mice weighing between 18 and 20 g are housed in groups of six. Porous chambers containing VEGF (2 μg/mL) in 0.5 mL of 0.8% w/v agar (containing heparin, 20 U/mL) are implanted subcutaneously in the flank of the mice (n=6 per group). VEGF induces the growth of vascularized tissue around the chamber. This response is dose–dependent and can be quantified by measuring the weight and TIE–2 levels of the tissue. Mice are treated either orally once daily with compounds or vehicle (PEG200 100%, 5 mL/kg) starting4–6 h before implantation of the chambers and continuing for 4 days. The animals are sacrificed for measurement of the vascularized tissues 24 h after the last dose. Tissue weight is taken and then a lysate prepared for TIE–2 ELISA analysis .Rat[1]Catheters are implanted into the femoral artery and vein of na?ve female rats strain OFA for BFH772, and BAW2881, or in the jugular vein and femoral artery in female Sprague–Dawley rats for compounds 4, 9, and 10. Animals are allowed to recover for 96 h and are housed in single cages with free access to food and water throughout the experiment. Female OFA rats received 2.5 mg/kg ofBAW2881 dissolved in ethanol/dimethylisosorbide/polyethylene glycol400/D5W (10/15/35/40 v/v) or 1 mg/kg of BFH772 dissolved in N–methyl pyrrolidone/polyethylene glycol200 (30:70, v/v) via injection into the femoral vein. D5W is glucose 5%/water (v/v). Oral administration: BAW2881 and BFH772 are formulated as a micronized suspension (dissolved/suspended in 0.5% carboxymethyl cellulose in distilled water) and administered by gavage to female OFA rats to deliver a dose of 25 mg/kg for BAW2881 or 3 mg/kg BFH772 (n=4 rats per group). For compounds 4, 9, and 10, female Sprague–Dawley rats at 8 weeks of age received an intraveno References:[1]. Bold G, et al. A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis. J Med Chem. 2016 Jan 14;59(1):132–46.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: tech@Address: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USA。

过氧化物酶体增殖物激活受体(PPAR) 是一类由配体激活的核转录因子,属Ⅱ型核受体超家族成员, 存在3种亚型，即PPARα、PPARδ、PPARγ，这三种亚型在结构上有一定的相似性，均含DNA结合区和配体结合区等。

PPAR与配体结合后被激活，与9-顺视黄酸类受体形成异二聚体，然后与靶基因的启动子上游的过氧化物酶体增殖物反应元件(peroxisome proliferator response element，PPRE)结合而发挥转录调控作用。

PPRE 由含相隔一个或两个核苷酸的重复序列AGGTCA组成。

与配体结合后，PPAR在DNA结合区发生变构，进而影响PPAR刺激靶基因转录的能力。

PPARδ几乎在所有组织中表达，浓度低于PPARα及PPARγ，直至最近以前尚未找到此一核受体的选择性配基。

PPARδ是代谢综合征（肥胖、胰岛素抵抗、高血压是与脂质紊乱有关的共同的病态表现）的一个新靶点。

有不少的研究表明：GW501516可作为PPARδ的特异激动剂用于研究。

参考网址：/cjh/2003/shownews.asp?id=156/conference/preview.php?kind_id=03&cat_name=ADA2001&title_id=59219 Regulation of Muscle Fiber Type and Running Endurance by PPARδplos biology，Volume 2 | Issue 10 | October 2004/plosonline/?request=get-document&doi=10.1371%2Fjournal.pbio.0020294NF-KB通路中的抑制剂好像有1.PDTC(pyrrolidine dithiocarbamate),是一种抗氧化剂，主要作用于IκB降解的上游环节（IκBα的磷酸化或IKK的活性水平），2.Gliotoxin 是一种免疫抑制剂，机制可能从多个环节阻断NF-KB的激活，如IκB的降解，NF-KB的核移位和与DNA的结合。

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收 稿 日期 ：０ ０１ －０ ２ １ ． ２ ２ 基 金 项 目 ： 怡 康 纳 制 药 中药 研 发 基 金 项 目（ Ｙ ４ ３ １ ． 卓 Ｚ ０００ ）
作者简介 ： 李富仁（ ９ ６一）， ， １５ 男 副教授 ， 主要从事药物作用机制研究
第 １ 期
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