EGFR (IC50 = 7.4 nM); ErbB2 (IC50 = 9 nM)

Canertinib 以剂量依赖性方式显着抑制 RaH3 和 RaH5 培养的黑色素瘤细胞的生长。 IC50 约为 0.8 μM，两种细胞系在 5μM 处理 72 小时后完全停止生长。治疗 24 小时内，指数生长的 RaH3 和 RaH5 细胞在细胞周期的 G1 期积累，与 1 μM canertinib 孵育时不诱导细胞凋亡。在这两种细胞系中，1 μM canertinib 可抑制 ErbB1-3 受体磷酸化，同时降低 Akt-、Erk1/2- 和 Stat3 活性[2]。
此外，canertinib 还可强烈刺激外泌体分泌[3]。

Canertinib 表现出增强的体内抗肿瘤活性，导致 A431 异种移植物生长延迟，口服给药后持续时间超过 50 天[1]。腹腔注射40 mg/kg/天的canertinib可显着抑制裸鼠体内人类恶性黑色素瘤异种移植物RaH3和RaH5的生长（图4）。治疗4天内，对黑色素瘤异种移植物的抗增殖作用就很明显。在治疗期间，这种效果进一步增强，肿瘤体积的差异证明了这一点，并在治疗 18 天内达到统计学显着性[2]。 CI-1033/Canertinib 在裸鼠中以 5 mg/kg 体重显示出针对 A431 异种移植物的令人印象深刻的活性。 CI-1033（20 至 80 mg/kg/d）在 H125 异种移植模型中实现了高度的肿瘤消退。口服给予 CI-1033 可显着抑制裸鼠 TT、TE6 和 TE10 异种移植物的生长，且无动物死亡且体重减轻<10%。

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体内活动。[1]
喹唑啉8和18/卡内替尼和吡啶并[3,2-d]嘧啶25对小鼠A431异种移植物进行了评估，结果见表3。8和18/Canertinib在口服14天后都显示出令人印象深刻的活性，但与其他类似物相比，衍生物18的效力要高得多（最佳剂量为5mg/kg/天）。吡啶并[3,2-d]嘧啶25的有效性很低，表明与其他测试的衍生物相比，其剂量效力非常低，尽管其溶解度相同。在表3所示的两个剂量水平下，18的基本等效抗肿瘤活性表明该化合物可能具有良好的治疗指数。作为化合物诱导毒性的指标，实验动物的体重减轻很小，在耐受剂量水平下小于10%。

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卡内替尼抑制体内黑色素瘤细胞增殖[2]
腹腔注射40mg/kg/天的canertinib显著抑制了裸鼠体内人类恶性黑色素瘤异种移植物RaH3和RaH5的生长（图4）。对黑色素瘤异种移植物的抗增殖作用在治疗4天内就已经可见，并且在整个治疗期间进一步增加，如通过肿瘤体积的差异所观察到的，在治疗18天内达到统计学意义（RaH3 P=0.021和RaH5 P=0.014）（图4A和B）。与未治疗的肿瘤相比，canertinib对RaH3和RaH5异种移植物的生长抑制也反映在肿瘤重量的显著降低上（图4C）。可检测到的副作用很轻微，与未经治疗的动物相比，接受治疗的小鼠体重减轻了不到8%，没有皮疹、腹泻或任何其他副作用的迹象，尽管接受了治疗，所有动物似乎都茁壮成长。然而，治疗组中有一只携带RaH5异种移植物的小鼠在第5天死亡，没有出现任何疾病迹象。

在 96 孔滤板中进行酶测定以确定 IC50。 20 mM Hepes，pH 7.4，50 mM 钒酸钠，40 mM 氯化镁，10 µM 三磷酸腺苷 (ATP)（含 0.5 mCi [³²P]ATP），20 mg 聚谷氨酸/酪氨酸，10 ng EGFR 酪氨酸激酶和抑制剂 (Canertinib) 的适当稀释度均包含在 0.1 mL 总体积中。除 ATP 外，所有成分均添加至孔中，并将板在 25°C 下摇动 10 分钟。添加 [³²P]ATP 后，将板在 25°C 下孵育 10 分钟以启动反应。添加 0.1 mL 20% 三氯乙酸 (TCA) 可终止反应。为了使底物沉淀，将板在 4°C 下保持至少 15 分钟。之后，用0.2 mL 10% TCA 和平板计数器测量的³²P 掺入量洗孔五次[1]。

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18/Canertinib和25。[1]
将化合物在DMSO中的储备溶液稀释到pH 2.6、6.67和10.75的磷酸盐缓冲液中。将溶液保持在37°C，在时间零点和其他时间点进行HPLC追踪，直至24小时。母体药物和胺水解产物的峰面积以t=0值的百分比计算。HPLC条件为：  柱，Zorbax SB-C18，4.6毫米×25厘米；流动相，0.45 M甲酸盐缓冲液（甲酸铵+甲酸，pH 3.45），80%乙腈，20%MilliQ水；梯度洗脱，起始水相/有机相比为1:9，在25分钟内变为100:0，并在100:0下再保持5分钟。流速为1.0 mL/min，检测波长为254 nm。 质谱分析。将化合物18/Canertinib和25在DMSO中的溶液加入到含有25μg EGF受体酪氨酸激酶蛋白（在20 mM Tris、150 mM NaCl、1 mM DTT、1 mM EDTA中）和少量蛋白酶抑制剂抑肽酶和亮肽的溶液中，并用75 mM碳酸氢铵（pH 7.5）稀释。在加入5%（v/v）乙酸90分钟后淬灭反应，纯化蛋白质并通过离心过滤浓缩。变性溶液（80%CH3CN，pH 2.5）中蛋白质-药物复合物的分子量通过配备低流量微ESI源的ESI-MS测定，该源以150 nL/min的速度运行。一部分药物结合蛋白被还原、烷基化并用胰蛋白酶消化。肽从0.3×15 mm Vydac C18柱中直接洗脱到质谱仪中，CH3CN的线性梯度为5γμL/min，如下所示：  5% 在10分钟内将溶剂B稀释至95%溶剂B（其中A=0.05%TFA/2%CH3CN，B=0.045%TFA/90%CH3CN）。

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酪氨酸激酶测定。[1]
如前所述纯化EGFR酪氨酸激酶。 在96孔滤板中进行IC50[app]测定的酶测定。总体积为0.1 mL，含有20 mM Hepes，pH 7.4，50 mM钒酸钠，40 mM氯化镁，10μM三磷酸腺苷（ATP），含有0.5 mCi[32P]ATP，20 mg聚谷氨酸/酪氨酸，10 ng EGFR酪氨酸激酶，以及适当稀释的抑制剂。将除ATP外的所有成分加入孔中，并在25°C下摇动培养板10分钟。通过加入[32P]ATP开始反应，并将平板在25°C下孵育10分钟。通过加入0.1 mL 20%三氯乙酸（TCA）终止反应。将板在4°C下保持至少15分钟，以使基材沉淀。然后用0.2mL 10%TCA洗涤孔五次，用Wallacβ平板计数器测定32P掺入量。

在 72 小时内，RaH3 和 RaH5 细胞暴露于逐渐升高的卡那替尼浓度 (0–10 μM)。悬浮在缓冲液中后，对细胞进行计数[2]。

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不可逆性测试方案。[1]
A431人表皮样癌细胞在6孔板中生长至约80%融合，然后在无血清培养基中孵育18小时。将重复的细胞组用2 mM的指定化合物处理2小时，作为不可逆抑制剂进行测试。然后用100 ng/mL EGF刺激一组细胞5分钟，并按照蛋白质印迹程序制备提取物。用温热的无血清培养基洗涤另一组细胞中的化合物，孵育2小时，再次洗涤，再孵育2个小时，再次清洗，然后再孵育4小时。然后用EGF刺激这组细胞，并使提取物与第一组细胞相似。

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Western印迹程序。[1]
通过在0.2 mL沸腾的Laemlli缓冲液（2%十二烷基硫酸钠、5%β-巯基乙醇、10%甘油和50 mM三羟甲基氨基甲烷（tris），pH 6.8）中裂解细胞制备提取物，并将裂解物加热至100°C 5分钟。裂解物中的蛋白质通过聚丙烯酰胺凝胶电泳分离，并电泳转移到硝化纤维上。将膜在10 mM Tris、pH 7.2、150 mM NaCl、0.01%叠氮化物（TNA）中洗涤一次，并在含有5%牛血清白蛋白和1%卵清蛋白的TNA中封闭过夜。用抗磷酸酪氨酸抗体（UBI，封闭缓冲液中1mg/mL）印迹膜2小时，然后在TNA中洗涤两次，一次在含有0.05%吐温-20洗涤剂和0.05%非检测P-40洗涤剂的TNA中，两次在TNA。然后将膜在含有0.1 mCi/mL[125I]蛋白A的阻断缓冲液中孵育2小时，然后如上所述再次洗涤。待印迹干燥后，将其装入胶片暗盒中，并暴露于X-AR X射线胶片1-7天。带强度用分子动力学激光密度计测定。

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Caco-2细胞通透性。[1]
化合物18/Canertinib和25在Caco-2细胞中进行了吸收和分泌转运→B） 基底外侧至心尖（B→A） 实验在25μM药物的并排扩散装置中进行。[14C]甘露醇用于监测细胞完整性，[3H]美托洛尔（人体吸收率为90-95%）30,31用作参考化合物。细胞在接种后第35或21、23或25天传代，平均TEER测量值为430−508。孵育溶液在Hank's平衡盐溶液（HBSS）中用2%乙醇和2%DMSO制备；顶端和基底外侧室的pH值分别为6.5和7.4。同时进行[3H]长春花碱的双向转运实验，以确认P-gp活性。25,26使用LC-MS/MS方法监测药物浓度；使用闪烁计数测量参考化合物。 [1]
使用接种后21天第21代Caco-2细胞进行了18/Canertinib 和25对P-糖蛋白转运的影响，平均TEER测量值为484。心尖至基底外侧（A→B） 基底外侧至心尖（B→A） 对照实验在供体室中用[3H]长春花碱在并排扩散装置中进行。将化合物（25μM）添加到B的顶端和基底外侧隔室中→研究其对[3H]长春花碱外排抑制作用的实验。环孢菌素（10μM）也用作阳性对照抑制剂，27,28和[14C]甘露醇用于监测细胞完整性。孵育溶液在Hank's平衡盐溶液（HBSS）缓冲液（顶部pH 6.5，底部pH 7.4）中制备，含有2%乙醇和2%DMSO作为共溶剂。[14C]甘露醇渗透性值表明，在这些研究中，细胞单层仍然存活。

Mice: Treatment with canertinib begins when tumors exhibit consistent growth. Groups for treatment and control are randomly assigned to the mice. Every mouse in the canertinib-treated RaH3 group (n = 4) and RaH5 group (n = 7) gets intraperitoneal injections five days a week of 1.2 mg canertinib (40 mg/kg/day) in 0.1 ml 0.15 M NaCl. The same regimen is followed for the intraperitoneal injection of vehicle only in the control RaH3 (n = 3) and RaH5 (n = 7) mice. The mice are sacrificed by cervical dislocation at the conclusion of the treatment period, following the removal and weighing of the tumors[2].

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In Vivo Chemotherapy. [1]
Immune-deficient mice were housed in microisolator cages within a barrier facility on a 12-h light/dark cycle and received food and water ad libitum. Animal housing was in accord with AAALAC guidelines. All experimental protocols involving animals were approved by the institutional animal care and use committee. The A431 epidermoid carcinoma was maintained by serial passage in nude mice (NCr nu/nu). Nude mice were also used as tumor host for anticancer agent evaluations against this tumor model. In each experiment, test mice weighing 18−22 g were randomized and implanted with tumor fragments in the region of the right axilla on day 0. Animals were treated with test compounds on the basis of average cage weight (6 mice/dose group) initiated when tumors reached approximately 100−150 mg in mass and continued for the period indicated in Table 3. Whenever possible test compounds were evaluated over a range of dose levels ranging from toxic to ineffective. [1]
The doses reported in Table 3 are the maximum doses that could be administered without exceeding the LD10, unless otherwise indicated. This maximum tolerated dose (MTD) allows comparisons to be made among the tested compounds at an equitoxic dose level. Derivatives 8 and 18/Canertinib were administered as solutions of the isethionate salt generated in situ by the addition of 1.5 equiv of aqueous isethionic acid followed by dilution to dosing volume with distilled water (final pH 4). Compound 25 was dissolved directly in 50 mM sodium lactate buffer, pH 4. Compound dosing solutions were prepared for 5 days at a time. Host body weight change data are reported as the maximum treatment-related weight loss in these studies. Calculations of tumor growth inhibition (% T/C) and tumor growth delay (T−C) were performed as described previously.

Pharmacokinetics [5]
Plasma pharmacokinetics was evaluated using population pharmacokinetic analysis on data from the 43 patients in this study combined with data from 29 patients in a second phase I study where patients were dosed once weekly for 3 weeks every month. Pharmacokinetic analysis was done using a one-compartment linear model: NONMEMV and ADVAN2. Peak CI-1033 concentrations were achieved 2 to 4 h after dosing and were dose proportional. Plasma clearance (Cl/F) averaged 266 L/h, whereas the volume of distribution (Vd/F) averaged 1,330 liters, resulting in an apparent plasma elimination half-life of 4 h. CI-1033 did not accumulate with repeated dosing, and there was no evidence to suggest that adverse events were associated with atypical systemic exposure within dose groups. Post hoc analysis suggested that systemic exposure is not dependent upon age, gender, race, weight, or surface area. These findings support once a day dosing without adjustment for body weight or surface area in adult patients.

Safety [5]
A summary of adverse events reported during course 1 included diarrhea (25 patients, 47%); rash (29 patients, 55%); mucositis (17 patients, 32%); nausea (20 patients, 38%); vomiting (16 patients, 32%); allergic reactions, including hives, periorbital edema, tongue edema, and asymptomatic wheezing (5 patients, 9%); thrombocytopenia (4 patients, 8%); and a miscellany of other toxicities (Table 2). There were no obvious cumulative toxicities as evidenced by the small number of grade 3 treatment-associated toxicities (1 thrombocytopenia, 1 dehydration, and 1 nausea) in subsequent cycles, and no patients discontinued the study due to treatment-related adverse events. Of those patients experiencing multiple events of rash, most were considered of the same intensity within a patient, and none were reported as worsening following additional courses. Investigator descriptions of rash were consistent with an acneiform or follicular appearance that increased in frequency at higher dose levels consistent with reports from other ERGR inhibitors. Gastrointestinal toxicities were the most predominant adverse events during the study: diarrhea (62%), nausea (47%), mucositis (32%), and vomiting (30%). These events were generally of grade 1 to 2 intensity and were manageable with early intervention and standard treatment.

Hypersensitivity reaction was not evident until the higher dose levels (≥560 mg). One patient at the 560 mg dose level experienced angioedema of the tongue accompanied by urticaria and skin welts 5 h post-dose. There were no respiratory manifestations, and this DLT was effectively managed with antihistamine, steroids, and dose reduction. A second patient in the 560 mg dose group experienced mild wheezing on days 4 to 5 that was considered related to underlying asthma. At the 650 mg dose level, one patient experienced pruritis of the hands on day 1 and mild wheezing on days 5 to 7 that did not require dose reduction. Another patient at 650 mg experienced mild periorbital edema, hives, and chest tightness on day 1 that was successfully treated with antihistamine.

Although thrombocytopenia was not frequently reported as a clinical toxicity, an analysis of platelet levels from laboratory data showed that one or more below normal readings were noted in 22 patients (42%): grade 1 to 2 in 16 patients, grade 3 in 5 patients, and grade 4 in 1 patient. Thrombocytopenia was considered dose limiting in two separate cases at 50 and 650 mg. The duration of thrombocytopenia coincided closely with the duration of CI-1033 treatment. There was no clear evidence of a dose relationship or a cumulative dose effect, but more grade 1 to 2 events (12 of 26 patients, 47%) were recorded at doses 350 to 750 mg. However, all five episodes of grade 3 thrombocytopenia occurred in the lower dose cohorts, confounding the association of dose with the observed degree of thrombocytopenia.

[1]. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem. 2000 Apr 6;43(7):1380-97.

[2]. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8.

[3]. Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer. 2019 Mar 30;18(1):52.

[4]. Progress in the discovery of compounds inhibiting orthopoxviruses in animal models. Antivir Chem Chemother. 2008;19(3):115-24.

[5]. Phase I clinical and pharmacodynamic evaluation of oral CI-1033 in patients with refractory cancer. Clin Cancer Res. 2007 May 15;13(10):3006-14.

Canertinib Dihydrochloride is the hydrochloride salt of an orally bio-available quinazoline with potential antineoplastic and radiosensitizing activities. Canertinib binds to the intracellular domains of epidermal growth factor receptor tyrosine kinases (ErbB family), irreversibly inhibiting their signal transduction functions and resulting in tumor cell apoptosis and suppression of tumor cell proliferation. This agent also acts as a radiosensitizing agent and displays synergistic activity with other chemotherapeutic agents.

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Canertinib is a quinazoline compound having a 3-chloro-4-fluoroanilino group at the 4-position, a propenamido group at the 6-position, and a 3-morpholinopropoxy group at the 7-position. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is a member of quinazolines, an organofluorine compound, a member of morpholines and a member of monochlorobenzenes.
Canertinib is a pan-erbB tyrosine kinase inhibitor which work against esophageal squamous cell carcinoma in vitro and in vivo. Canertinib treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET.

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Drug Indication
Investigated for use/treatment in breast cancer and lung cancer.

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Mechanism of Action
CI-1033 effectively inhibits the growth of esophageal squamous cell carcinoma which co-expresses both EGFR and HER2 with the inhibition of phosphorylation of both MAPK and AKT. Some studies suggest that CI-1033 holds significant clinical potential in esophageal cancer.

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4-Anilinoquinazoline- and 4-anilinopyrido[3,2-d]pyrimidine-6-acrylamides substituted with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reaction of the corresponding 6-amines with acrylic acid or acrylic acid anhydrides. In the pyrido[3,2-d]pyrimidine series, the intermediate 6-amino-7-alkylamines were prepared from 7-bromo-6-fluoropyrido[3,2-d]pyrimidine via Stille coupling with the appropriate stannane under palladium(0) catalysis. This proved a versatile method for the introduction of cationic solubilizing side chains. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Quinazoline analogues with 7-alkoxyamine solubilizing groups were potent irreversible inhibitors of the isolated EGFR enzyme, with IC(50[app]) values from 2 to 4 nM, and potently inhibited both EGFR and erbB2 autophosphorylation in cells. 7-Alkylamino- and 7-alkoxyaminopyrido[3,2-d]pyrimidines were also irreversible inhibitors with equal or superior potency against the isolated enzyme but were less effective in the cellular autophosphorylation assays. Both quinazoline- and pyrido[3,2-d]pyrimidine-6-acrylamides bound at the ATP site alkylating cysteine 773, as shown by electrospray ionization mass spectrometry, and had similar rates of absorptive and secretory transport in Caco-2 cells. A comparison of two 7-propoxymorpholide analogues showed that the pyrido[3,2-d]pyrimidine-6-acrylamide had greater amide instability and higher acrylamide reactivity, being converted to glutathione adducts in cells more rapidly than the corresponding quinazoline. This difference may contribute to the observed lower cellular potency of the pyrido[3,2-d]pyrimidine-6-acrylamides. Selected compounds showed high in vivo activity against A431 xenografts on oral dosing, with the quinazolines being superior to the pyrido[3,2-d]pyrimidines. Overall, the quinazolines proved superior to previous analogues in terms of aqueous solubility, potency, and in vivo antitumor activity, and one example (CI 1033) has been selected for clinical evaluation.[1]

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The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.[2]

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Intercellular communication between cellular compartments within the tumor and at distant sites is critical for the development and progression of cancer. Exosomes have emerged as potential regulators of intracellular communication in cancer. Exosomes are nanovesicles released by cells that contain biomolecules and are exchanged between cells. Exchange of exosomes between cells has been implicated in a number of processes critical for tumor progression and consequently altering exosome release is an attractive therapeutic target. Here, we review current understanding as well as gaps in knowledge regarding regulators of exosome release in cancer.[3]

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Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, or used to treat an occasional serious orthopoxvirus infection, such as disseminated vaccinia complication following exposure to the live virus vaccine. Recently, considerable progress has been made in the discovery of novel antiviral agents found active against orthopoxviruses in vivo. This includes the development of new animal models or refinement of existing ones for compound efficacy testing. Current mouse models employ ectromelia, cowpox and vaccinia (WR and IHD strains) viruses with respiratory (lung) or tail lesion infections commonly studied. Rabbitpox and vaccinia (WR strain) viruses are available for rabbit infections. Monkeypox and variola viruses are used for infecting monkeys. This review describes these and other animal models, and covers compounds found active in vivo from 2003 to date. Cidofovir, known to be active against orthopox virus infections prior to 2003, has been studied extensively over recent years. New compounds showing promise are orally active inhibitors of orthopoxvirus infections that include ether lipid prodrugs of cidofovir and (S)-HPMPA, ST-246, N-methanocarbathymidine (N-MCT) and SRI 21950 (a 4'-thio derivative of iododeoxyuridine). Another compound with high activity but requiring parenteral administration is HPMPO-DAPy. Further development of these compounds is warranted.[4]

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Purpose: To determine the tolerability and pharmacokinetics of CI-1033 given daily for 7 days of a 21-day cycle. Tumor response and changes in erbB receptor tyrosine kinase activity in tumor and skin tissue were examined, and modulation of potential biomarkers in plasma was explored. Design: This was a dose-finding phase I study in patients with advanced solid malignancies. Patients were evaluated for safety, pharmacokinetics, and tumor response. Pharmacodynamic markers, such as Ki67, p27, and erbB receptor status, were assessed in tumor and skin tissue using immunohistochemical and immunoprecipitation methodologies. Plasma biomarkers HER2, vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 were evaluated using immunologic techniques. Results: Fifty-three patients were enrolled in the study. Dose-limiting toxicity (emesis, persistent rash, and mouth ulcer) was observed at 750 mg. The maximum tolerated dose was 650 mg. There were no confirmed objective responses. CI-1033 treatment showed down-regulation of epidermal growth factor receptor, HER2, and Ki67 in a variety of tumor tissues and up regulation of p27 in skin tissue. Plasma HER2 was reduced following CI-1033 administration, but no consistent change in vascular endothelial growth factor, interleukin-8, or matrix metalloproteinase-9 was noted. CI-1033 plasma concentrations were proportional to dose. Conclusion: The safety and pharmacokinetic profile of CI-1033 was favorable for multidose oral administration. Evidence of modulation of erbB receptor activity in tumor and skin tissue was accompanied by changes in markers of proliferation and cell cycle inhibition. Additional clinical trials are warranted in defining the role of CI-1033 in the treatment of cancer and further assessing the utility of antitumor markers.[5]

C24H27CL3FN5O3

558.8603

557.116

C, 51.58; H, 4.87; Cl, 19.03; F, 3.40; N, 12.53; O, 8.59

289499-45-2

Canertinib;267243-28-7

156413

Light yellow to green yellow solid powder

1.355g/cm3

691ºC at 760mmHg

188-190℃

371.7ºC

6.08E-19mmHg at 25°C

1.649

6.079

88.61

4

8

9

36

671

0

ClC1=C(C([H])=C([H])C(=C1[H])N([H])C1C2=C([H])C(=C(C([H])=C2N=C([H])N=1)OC([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H])N([H])C(C([H])=C([H])[H])=O)F.Cl[H].Cl[H]

JZZFDCXSFTVOJY-UHFFFAOYSA-N

InChI=1S/C24H25ClFN5O3.2ClH/c1-2-23(32)30-21-13-17-20(14-22(21)34-9-3-6-31-7-10-33-11-8-31)27-15-28-24(17)29-16-4-5-19(26)18(25)12-16;;/h2,4-5,12-15H,1,3,6-11H2,(H,30,32)(H,27,28,29);2*1H

N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide;dihydrochloride

CI1033; CI1033; CI-1033; Canertinib dihydrochloride; Canertinib HCl; Canertinib dihydrochloride [USAN]; PD-0183805; PD183805; PD183,805; PD183,805; PD183,805; Canertinib HCl; Canertinib dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 62.5~100 mg/mL (111.8~178.9 mM)
Water: ~33 mg/mL (~59.1 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (3.72 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (3.72 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: 2.08 mg/mL (3.72 mM) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 10 mg/mL (17.89 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。