AS-1763
目录号 : GC63896
AS-1763 是一种有效、选择性、非共价、口服的布鲁顿酪氨酸激酶抑制剂（IC50 = 0.85 nM）。
Cas No.:2227211-00-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AS-1763 is a potent, selective, noncovalent, and orally available inhibitor of Bruton’s tyrosine kinase (IC50 = 0.85 nM).
[1]. Kawahata W, et al. Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton’s Tyrosine Kinase. J Med Chem. 2021 Oct 14;64(19):14129-14141.
| Cas No. | 2227211-00-7 | SDF | Download SDF |
| 分子式 | C33H31FN6O3 | 分子量 | 578.64 |
| 溶解度 | 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7282 mL | 8.641 mL | 17.2819 mL |
| 5 mM | 0.3456 mL | 1.7282 mL | 3.4564 mL |
| 10 mM | 0.1728 mL | 0.8641 mL | 1.7282 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。
Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase
J Med Chem 2021 Oct 14;64(19):14129-14141.PMID:34529443DOI:10.1021/acs.jmedchem.1c01279.
Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.
Investigating The Impact of Covalent and Non-covalent Binding Modes of Inhibitors on Bruton's Tyrosine Kinase in the Treatment of B Cell Malignancies-Computational Insights
Curr Pharm Biotechnol 2022 Jun 17.PMID:35718983DOI:10.2174/1389201023666220617151552.
Background Bruton tyrosine kinase plays a key role in the survival, proliferation, activation and differentiation of B-lineage cells and the signaling of other receptors. It is overexpressed and constitutively active in the pathogenesis of B cell malignancies and has therefore become a target for therapeutic intervention. Some success has been achieved in the discovery of small molecules especially in the development of irreversible inhibitors. However, these inhibitors are punctuated by off target effects and have also become less effective in patients with mutations at Cys481. This motivated the search for inhibitors with improved efficacy and different binding modes. Methods In this study we employed two new second generation inhibitors with different binding modes, Zanubrutinib and AS-1763, which are at various levels of clinical trials to highlight the molecular determinants in the therapeutic inhibition of BTK through computational studies. Results This study revealed Zanubrutinib and AS-1763 exhibited free total binding energies of -98.76±4.63kcal/mol and -51.81±9.94kcal/mol respectively with Zanubrutinib engaging in peculiar hydrogen bond interactions with the hinge residues Glu475 and Met477 including Asn484, and Tyr485 whiles AS-1763 engaged Lys430, Asp539, and Arg525. These residues contributed the most towards the free total binding energy with energies above -1.0kcal/mol. The compounds further interacted differentially with other binding site residues through pi-alkyl, pi-cation, pi-anion, pi-pi-T-shaped, pi-sigma, pi-sulfur and pi-donor hydrogen bonds and Van der Waals interactions. These interactions resulted in differential fluctuations of the residues with consequential unfolding of the protein. Conclusion Insights herein would be useful in guiding the discovery of more selective and potent small molecules.