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| ARRY-380Tyrosine kinase HER2 and p95-HER2 inhibitor |
Sample solution is provided at 25 µL, 10mM.
Nature.2017 Jan 19;541(7637):417-420.
Nature.2018 Nov;563(7731):407-411.Nature.2018 Jun 13.Nature.2018 Jun 27.Nature.2018 Mar 29;555(7698):673-677.Nature.2017 Sep 7;549(7670):96-100.Nature.2016 Apr 21;532(7599):398-401.
Science.2016 Aug 5;353(6299)594-8Nat Nanotechnol.2017 Dec;12(12):1190-1198.Nature Biotechnology.2017 Jun;35(6):569-576Nat Med.2018 Sep 17.Cell.2018 Dec 21. pii: S0092-8674(18)31561-7.Cell.Available online 25 October 2018.Cell.2018 Sep 27. pii: S0092-8674(18)31183-8.Cell.2018 Jun 28;174(1):172-186.e21.Cell.2018 Feb 22;172(5):1007-1021.e17.Cell.2017 Nov 30;171(6):1284-1300.e21.Cell.2017 Aug 17. pii: S0092-8674(17)30869-3.Cell.2017 Jul 13;170(2):312-323Nat Med.2018 Jan 29.Nat Med.2017 Nov;23(11):1342-1351.Cell.2017 Apr 6;169(2):286-300.Cell.2015 Aug 27;162(5):987-1002.Cell.2015 Feb 12;160(4):729-44.Nature Medicine.2017 Apr;23(4):493-500.Cancer Cell.2018 May 14;33(5):905-921.e5.Cancer Cell.2018 Apr 9;33(4):752-769.e8.Cancer Cell.2018 Mar 12;33(3):401-416.e8.Cancer Cell.2017 Aug 14;32(2):253-267.e5.Nat Methods.2018 Jul;15(7):523-526.Cell Stem Cell.2018 May 3;22(5):769-778.e4.Cell Stem Cell.2017 Nov 20. pii: S1934-5909(17)30375-2.Quality Control & MSDS
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- Purity = 99.55%
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- NMR (Nuclear Magnetic Resonance)
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- Datasheet
Chemical structure
| Description | ARRY-380 is an orally bioavailable, potent, selective, small-molecule inhibitor of tyrosine kinase HER2 and p95-HER2 with an IC50 of 8 and 7 nM, respectively. | |||||
| Targets | p95-HER2 | HER2 | EGFR | |||
| IC50 | 7 nM | 8 nM | 4 μM | |||
| Cell experiment [1]: | |
Cell lines | BT474 cells, NIH-3T3 cells |
Preparation method | Soluble in DMSO >28.5mg/mL. 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 | N/A |
Applications | ARRY-380 is an orally active, selective, small molecule inhibitor of ErbB2(human epidermal growth factor receptor-2). Its activity (IC50) against ErbB2 enzyme is 14 nM and it inhibits the phosphorylation of ErbB2 in BT474 cells in culture with an IC 50 of 21 nM. ARRY-380 also potently inhibits phosphorylation of AKT(protein kinase B), induces apoptosis and inhibits growth of BT474 cells in vitro. Marked tumor growth inhibition has been demonstrated in NIH-3T3 cells stably transfected with constitutively active ErbB2 kinase (3T3-rErbB2). |
| Clinical experiment [2]: | |
Disease models | Patients with HER2-positive cancers (including HER2+MBC(Metastatic Breast Cancer)) |
Dosage form | Dose-escalation cohorts(HER2+ cancer): A starting dose of 25 mg BID(twice-daily)was utilized with additional cohorts at planned dose levels of 50, 100, 200, 300, 500, 650 and 800 mg dosing in a fed state in continuous 28-day cycles (600mg BID was the MTD(maximum tolerated dose)) in Cycle 1.expansion cohort(HER2+MBC): 600mg BID in continuous 28-day cycles in Cycle 2. |
Application | ARRY-380 had a lower incidence and severity of diarrhea and rash than that typically associated with current dual HER2/EGFR (Epidermal Growth Factor Receptor) inhibitors and showed notable anti-tumor activity in heavily pretreated HER2+MBC patients, supporting its continued development. |
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]. Pheneger, T., et al., In vitro and in vivo activity of ARRY-380: A potent, small molecule inhibitor of ErbB2. Presented at the American Association of Cancer Research 100th Annual Meeting Apr 18-22, 2009; Cancer Res 69 (abstr 1795). [2]. Moulder SL1, Borges VF2, et al, Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC). Clin Cancer Res. 2017 Jul 15;23(14):3529-3536. doi: 10.1158/1078-0432.CCR-16-1496. Epub 2017 Jan 4. | |
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| Cas No. | 937265-83-3 | SDF | Download SDF |
| Synonyms | ARRY380; ARRY 380 | ||
| Chemical Name | 6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazolin-4-amine | ||
| Canonical SMILES | CC1=C(C=CC(=C1)NC2=NC=NC3=C2C=C(C=C3)C4=CC=C(O4)CNCCS(=O)(=O)C)OC5=CC6=NC=NN6C=C5 | ||
| Formula | C29H27N7O4S | M.Wt | 569.63 |
| Solubility | ≥28.5mg/mL in DMSO | Storage | Store at -20°C |
| Physical Appearance | A solid | Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size:ship with RT , or blue ice upon request |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
IC50: 8 nM (HER2)
HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. ARRY-380 is an orally bioavailable inhibitor of the human epidermal growth factor receptor tyrosine kinase ErbB-2 (also called HER2) with potential antineoplastic activity.
In vitro: ARRY-380 is reported to be a reversible, ATP-competitive inhibitor with nanomolar activity against HER2 enzyme. In cell-based assays, ARRY-380 is ~500-fold selective for HER2 vs. EGFR and is equipotent against truncated p95-HER2 [1].
In vivo: ARRY-380 treatment significantly enhances survival in two ErbB2 driven intracranial tumor xenograft models, with superior activity compared to other ErbB2 agents in these studies. Additionally, ARRY-380 has demonstrated durable clinical activity in heavily pre-treated patients with ErbB2+ MBC. These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases. These preclinical and clinical data suggest that ARRY-380 may provide benefit to patients with ErbB2+ MBC with brain metastases and warrants further study [2].
Clinical trial: In a phase 1 clinical trial, 15 patients have been treated in 5 dosing cohorts at doses of 25 to 300 mg BID. No DLTs have been observed and drug-related adverse events have included Grade 1 nausea, rash and fatigue and Grade 2 fatigue in 2 patients at the 200 mg BID dose level. Preliminary PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours and a mean t1/2 of 4.6 hours across all cohorts. Two patients with HER2+ breast cancer have had stable disease for ≥ 4 months with no significant toxicity. One of these two patients had a notable reduction in liver metastases (28%) after 2 cycles of ARRY-380 and is currently on study.These findings indicate ARRY-380 has demonstrated an acceptable safety and PK profile and preliminary signs of clinical benefit. Dose escalation continues to determine the MTD [3].
References:[1] S. L. Moulder, V. Borges, S. K. L. Chia, T. Baetz, E. Barrett, J. Garrus, K. Guthrie, C. Kass, E. Laird, J. Lyssikatos, F. Marmsater, E. Wallace. ARRY-380, a Selective HER2 Inhibitor: From Drug Design to Clinical Evaluation. Poster of AACR-NCI-EORTC, Nov 12-16, 2011, San Francisco, CA.[2] Victoria Dinkel, Deborah Anderson, Shannon Winski, Jim Winkler, Kevin Koch and Patrice Lee. ARRY-380, a potent, small molecule inhibitor of ErbB2, increases survival in intracranial ErbB2+ xenograft models in mice. Poster available at www.arraybiopharma.com[3] S. Chia, T. Baetz, S. D"Aloisio, G. Fernetich, B. Freeman, E. Barrett, C. Kass, J. Kang, B. Sajan, S. Moulder, and J. Garrus. A Phase 1 Study To Assess the Safety, Tolerability and Pharmacokinetics of ARRY-380 – An Oral Inhibitor of HER2. Cancer Res 2009;69(24 Suppl):Abstract nr 5111.
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教。
版主laocao留言:
患者的年龄，病史，症状，辅助检查传上来，便于进一步讨论，谢谢！
（第1张图和第2张图是经旋转后方向恰好相反的两张图，上矢状窦等静脉也显示了）
女患，70岁，大专毕业，我院退休药师。7-8年前患脑梗（具体不详）。记忆力差5-6年，近记忆为著，几次做饭后忘记关火，将炉具的台板（玻璃的）烧裂。近5-6年来，病人每年住院彻底检查治疗1次（主要是使用活血化瘀及营养脑细胞药）。平素，病人双耳听力略差，睡眠欠佳、便秘、尿频，偶从卧位坐起时视蒙。既往有时血压略高，未降压治疗。本次为“通血管”再来住院。查体：血压：140/80mmHg,双耳听力略差，近记忆力差，但智力（MMSE：26分)正常，颅神经未见异常，四肢肌力、感觉未见异常，植物神经未查，双掌颌反射（+），双下肢病理反射均阴性。血常规：淋巴细胞比率略高，余均正常；尿常规、心电图、癌胚抗原均正常；凝血四项：除凝血酶时间略长外均正常；生化全项：除总胆固醇略高外均正常；超声心动图：老年瓣退行性改变，左室舒张功能减退，房膜瘤可能。彩超：双侧颈动脉粥样硬化形成。头MRA:右大脑中动脉及其分支未显示。
问题：1MRI怎么会这样逍遥？病人无肢体瘫，生活自理如常人。
2为明确头MRA:右大脑中动脉及其分支未显示的病因和程度，除做DSA外，还需做什么？
3如不做DSA，给他订类药、阿斯匹林及活血化瘀的中药可不可以？
