AG-024322
目录号 : GC62830
AG-024322 是一种有效的 ATP 竞争性的 pan-CDK 抑制剂，抑制 CDK1， CDK2， CDK4 的 Ki 值在 1-3 nM 范围内。AG-024322 在体内表现出广谱抗肿瘤活性和清晰的靶标调控。AG-024322 诱导细胞凋亡 (apoptosis)。
Cas No.:837364-57-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
AG-024322 is a potent ATP-competitive pan-CDK inhibitor against cell cycle kinases CDK1, CDK2, and CDK4 with Ki values in the 1-3 nM range[1]. AG-024322 displays broad-spectrum anti-tumor activity and clear target modulation in vivo. AG-024322 induces cell apoptosis[3].
AG-024322 (0.1-30 μM; 24 hours) is less toxic at concentrations below 3 µM, the viability of human PBMCs as measured by ATP content with a TC50 value of 1.4 µM for human PBMCs[2].AG-024322 (0-120 nM) exhibits growth inhibition effects on HCT-116 cells. It is slightly less potent in the functional cellular assay with an IC50 of 120 nM[2].
AG-024322 (intravenous infusion; 2, 6, and 10 mg/kg; 5 days) exhibits no-adverse-effect at 2 mg/kg with mean plasma AUC (0-24.5) of 2.11 g.h/mL. At 6 mg/kg produces pancytic bone marrow hypocellularity, lymphoid depletion. And vascular injury at the injection site renal tubular degeneration occurs at 10 mg/kg[1].AG-024322 (20 mg/kg) inhibits the growth of established human tumor xenografts of different origins with tumor growth inhibition (TGI) ranging from 32% to 86.4%.It also exhibits anti-tumor effects as a dose-pdependent manner[3].AG-024322 (20 mg/kg) causes a 65% TGI in the MV522 tumor model. It results a 52% TGI at 1/2 of the maximum tolerated dose (MTD) and only slight anti-tumor activity at 1/4 of the MTD[3].
[1]. Brown AP, et al. Toxicity and toxicokinetics of the cyclin-dependent kinase inhibitor AG-024322 in cynomolgus monkeys following intravenous infusion.Cancer Chemother Pharmacol. 2008 Nov;62(6):1091-101.
[2]. Jessen BA,et al. Peripheral white blood cell toxicity induced by broad spectrum cyclin-dependent kinase inhibitors.J Appl Toxicol. 2007 Mar-Apr;27(2):133-42.
[3]. Cathy C. Zhang, et al. AG-024322 is a multi-targeted CDK inhibitor with potent antitumor activity in vivo. Cellular and Molecular Biology 53: Cell Cycle Control and Cancer 1
| Cas No. | 837364-57-5 | SDF | |
| 分子式 | C23H20F2N6 | 分子量 | 418.44 |
| 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 | 2.3898 mL | 11.9491 mL | 23.8983 mL |
| 5 mM | 0.478 mL | 2.3898 mL | 4.7797 mL |
| 10 mM | 0.239 mL | 1.1949 mL | 2.3898 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。
Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance
Mol Cancer Ther 2016 Oct;15(10):2273-2281.PMID:27496135DOI:10.1158/1535-7163.MCT-16-0300.
Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies of ATP-competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATP-binding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs. Mol Cancer Ther; 15(10); 2273-81. ©2016 AACR.
Toxicity and toxicokinetics of the cyclin-dependent kinase inhibitor AG-024322 in cynomolgus monkeys following intravenous infusion
Cancer Chemother Pharmacol 2008 Nov;62(6):1091-101.PMID:18509643DOI:10.1007/s00280-008-0771-1.
Purpose: Cyclin-dependent kinases (CDKs) play a significant role in the control of cell-cycle progression and exhibit aberrant regulation in various neoplastic diseases. AG-024322 is a potent inhibitor of CDK1, CDK2, and CDK4 that produces cell-cycle arrest and antitumor activity in preclinical models. This study evaluated the toxicity of AG-024322 when given by intravenous (IV) infusion to cynomolgus monkeys, including reversibility of effects. Methods: Male and female monkeys received AG-024322 by 30-min IV infusion once daily for 5 days at doses of 2, 6, and 10 mg/kg (24, 72, and 120 mg/m(2), respectively). Controls received vehicle alone which was aqueous 5% dextrose, pH 3.8. Three animals/sex/group were necropsied on day 6, and two animals/sex/group at 6 and 10 mg/kg were necropsied on day 22 (reversal cohort). Doses were based upon the results of a dose range-finding study in monkeys; decreased white blood cells occurred at > or =3 mg/kg and 12 mg/kg produced central nervous system effects and was above the maximum-tolerated dose. Results: No deaths occurred and clinical signs of toxicity, including swelling at the IV administration site, were seen at > or =6 mg/kg. AG-024322 at > or =6 mg/kg produced pancytic bone marrow hypocellularity, lymphoid depletion, and vascular injury at the injection site. Renal tubular degeneration occurred at 10 mg/kg. These changes were either reversible or in a process of repair following the 17-day recovery period. Hematology changes included decreases in reticulocytes and/or granulocytes at > or =6 mg/kg, which were reversible and consistent with changes in the bone marrow. Lymphoid and bone marrow depletion are consistent with pharmacologic inhibition of CDKs by AG-024322 and were expected findings. On day 22, vacuolar degeneration of pancreatic acinar cells with increased serum amylase and lipase levels occurred in one female at 10 mg/kg. Neither sex-related differences in toxicokinetics nor plasma accumulation over 5 days of dosing were seen. Terminal phase overall mean half-life on day 5 ranged from 6.69 to 8.87 h (across dose levels) and was not dose dependent. Conclusion: The no-adverse-effect dose of AG-024322 was 2 mg/kg and associated with overall mean plasma AUC(0-24.5) of 2.11 microg h/mL.
Graphic rule for drug metabolism systems
Curr Drug Metab 2010 May;11(4):369-78.PMID:20446902DOI:10.2174/138920010791514261.
Using graphic rules to deal with kinetic systems is an elegant approach by combining the graph representation (schematic representation) and rigorous mathematical derivation. It bears the following advantages: (1) providing an intuitive picture or illuminative insights; (2) helping grasp the key points from complicated details; (3) greatly simplifying many tedious, laborious, and error-prone calculations; and (4) able to double-check the final results. In this mini review, the non-steady state graphic rule in enzyme-catalyzed kinetics and protein-folding kinetics was extended to cover drug-metabolic systems. As a demonstration, a step-by-step illustration is presented showing how to use the graphic rule to derive the concentrations of the parent drug and its metabolites vs. time for the seliciclib, vildagliptin, and cyclin-dependent kinase inhibitor (AG-024322) metabolic systems, respectively. It can be seen from these paradigms that the graphic rule is particularly useful to analyze complicated drug metabolic systems and ensure the correctness of the derived results. Meanwhile, the intuitive feature of graphic representation may facilitate analyzing and classifying drug metabolic systems; e.g., according to their directed graphs, the metabolism of seliciclib and the metabolism of vildagliptin can be categorized as 0-->5 mechanism while that of AG-024322 as 0-->4-->3 mechanism.