ARQ 531
(Synonyms: MK-1026) 目录号 : GC31679
Nemtabrutinib (ARQ 531, MK-1026) is an ATP-competitive tyrosine kinase inhibitor designed to target BTK with an IC50 of 0.85 nM. It also has a distinct kinase selectivity profile with strong inhibitory activity against several key oncogenic drivers from TEC, Trk and Src family kinases.
Cas No.:2095393-15-8
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Nemtabrutinib (ARQ 531, MK-1026) is an ATP-competitive tyrosine kinase inhibitor designed to target BTK with an IC50 of 0.85 nM. It also has a distinct kinase selectivity profile with strong inhibitory activity against several key oncogenic drivers from TEC, Trk and Src family kinases.
ARQ 531 potently inhibited BTK (IC50 = 0.85 nM), the binding potency was accompanied by long residence time (51 min). ARQ 531 selectively inhibits BCR signaling dependent PI3K/AKT/mTOR, Ras/Raf/Erk and Rap-GTPase-Cofilin pathways in TMD8 cells. It potently inhibits proliferation of hematological malignant cell lines both sensitive and resistant to ibrutinib addicted to BCR signaling[1]. Unlike ibrutinib, ARQ 531 suppressed both the upstream activating signals (via inhibition of a select member of Src kinase family) and the downstream signaling pathways (via pAKT and pERK kinases). In GCB-DLBCL cell lines (SUDHL-4 and DOHH-2), ARQ 531 potently suppressed expression of anti-apoptotic c-Myc and BCL6 oncoproteins in a dose dependent fashion, and concomitantly induced apoptotic cleavage of PARP protein[2].
ARQ 531 has potent anti-tumor activity was observed in both ABC-DLBCL and GCB-DLBCL mouse xenograft models[1]. ARQ 531 crosses the blood, brain-barrier[2]. In a single oral dose study of 10mg/kg in monkeys, the bioavailability of ARQ 531 is 72.4% with a Cmax of 9 μM and a half-life greater than 24 hours[3].
[1] Sudharshan Eathiraj, et al. EHA Congress. 2017, ePoster number: E1400. [2] Sudharshan Eathiraj, et al. AACR Cancer Res 2018. 78(13 Suppl):Abstract nr 1963. [3] Sean D. Reiff, et al. Blood. 2016, 128:3232.
Cell experiment: | Biochemical inhibition assay is measured using full length BTK constructs of wild type or C481S mutant. Profiling on 236 kinases identifies 45 kinases with >50% inhibition at 200 nM concentration of ARQ 531. Subsequently, the potency of this ATP competitive inhibitor is determined on such kinases at the physiological 1 mM ATP concentration cells are treated with increasing concentrations of inhibitors in SUDHL-4 for 2 hours, following stimulation with either anti-IgM or growth factors cells are lysed for Western blot analysis[1]. |
Animal experiment: | Mice[1]Six week old female CB-17 SCID mice (1-2 weeks) are used. Mice are housed in sterile micro isolator cages, five mice per cage and receive food and water ad libitum. Female SCID mice are implanted subcutaneously with 8x106 TMD8 cells in 0.2 mL HBSS with 50% standard concentration BD matrigel in the upper right flank area. Mice are monitored and staged on day 14 (post injection of tumor cells) when size reaches approximately 400 mg. Oral daily dosing with ARQ 531 at 100 mg/kg, vinblastine or vehicle began on stage day. Tumor measurements and body weights are collected three times a week. In vivo Target and pathway inhibition is studied in mouse TMD8 xenograft model. Percent inhibition relative to the vehicle control is determined using densitometry analysis and the intensity of actin band is used as a loading control and the percentage of vehicle group is designated as 100%. DBA1/J mice are immunized with collagen to develop the arthritis, following the onset of arthritis, mice are randomized into treatment groups. Treatment is initiated by oral dosing of ARQ 531 at 25, 50 and 75 mg/kg and continued daily through arthritis day 14. Clinical scores are assessed for each of the paws on study arthritis days 1-15. Dexamethasone at 3 mg/kg is used as a control[1]. |
References: [1]. S Eathiraj, et al. Targeting Ibrutinib-Resistant BTK-C481S Mutation with ARQ 531, a Reversible Non-Covalent Inhibitor of BTK. Clinical Lymphoma Myeloma & Leukemia, 2016, 16: S47-S48. | |
| Cas No. | 2095393-15-8 | SDF | |
| 别名 | MK-1026 | ||
| Canonical SMILES | O=C(C1=C(C=C(OC2=CC=CC=C2)C=C1)Cl)C3=CNC4=NC=NC(N[C@@H]5CC[C@@H](CO)OC5)=C34 | ||
| 分子式 | C25H23ClN4O4 | 分子量 | 478.93 |
| 溶解度 | DMSO : ≥ 50 mg/mL (104.40 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 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。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.088 mL | 10.4399 mL | 20.8799 mL |
| 5 mM | 0.4176 mL | 2.088 mL | 4.176 mL |
| 10 mM | 0.2088 mL | 1.044 mL | 2.088 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet