PHA-793887
(Synonyms: 3-甲基-N-[1,4,5,6-四氢-6,6-二甲基-5-[(1-甲基-4-哌啶基)甲酰基]吡咯并[3,4-C]吡唑-3-基]丁酰胺) 目录号 : GC15047A CDK inhibitor
Cas No.:718630-59-2
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment [1]: | |
Cell lines |
A2780 cells |
Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
Reaction Conditions |
0.1 nM ~ 1 μM; 72 hrs |
Applications |
In A2780 cells, PHA-793887 (1 μM) induced a decrease in the S phase, a subsequent increase of the G1 phase and a slight accumulation of the G2/M phase. |
Animal experiment [1]: | |
Animal models |
Mouse xenograft models of human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma |
Dosage form |
10, 20 and 30 mg/kg; i.v.; q.d., for 10 days |
Applications |
In the human ovarian A2780, colon HCT-116, and pancreatic BX-PC3 carcinoma xenograft models, PHA-793887 (10 ~ 30 mg/kg) significantly inhibited tumor growth. |
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]. Brasca MG, Albanese C, Alzani R, Amici R, Avanzi N, Ballinari D, Bischoff J, Borghi D, Casale E, Croci V, Fiorentini F, Isacchi A, Mercurio C, Nesi M, Orsini P, Pastori W, Pesenti E, Pevarello P, Roussel P, Varasi M, Volpi D, Vulpetti A, Ciomei M. Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing. Bioorg Med Chem. 2010 Mar 1;18(5):1844-53. |
Description:
IC50: PHA-793887 is a novel and potent inhibitor of CDK2, CDK5 and CDK7 with IC50 values of 8 nM, 5 nM and 10 nM, respectively.
Cyclin dependent kinases (CDKs) are a family of serine/threonine kinases that, in concert with cyclins (positive regulators) and natural inhibitors (CDKI), control the cell cycle progression.1Deregulation of the activity of CDKs, mainly due to alterations of expression and/or genetic mutations of cyclins, CDKs, CDKIs and other components of the retinoblastoma protein (pRB) pathway, has been reported in more than 90% of human neoplasms.
In vitro: PHA-793887 was found to be cytotoxic for leukemic cell lines in vitro, with IC50 ranging from 0.3 to 7 μM (mean: 2.9 μM), regardless of any specific chromosomal aberration. At these doses, the drug was not cytotoxic for normal unstimulated peripheral blood mononuclear cells or CD34+ hematopoietic stem cells. Moreover, in colony assays PHA-793887 showed very high activity against leukemia cell lines, with an IC50<0.1 μM (mean: 0.08 μM), indicating that it has efficient and prolonged antiproliferative activity. PHA-793887 induced cell-cycle arrest, inhibited Rb and nucleophosmin phosphorylation, and modulated cyclin E and cdc6 expression at low doses (0.2-1 μM) and induced apoptosis at the highest dose (5 μM) [1].
In vivo: PHA-793887 was also effective in vivo in both subcutaneous xenograft and primary leukemic disseminated models that better mimic naturally occurring human disease. Interestingly, in one disseminated model derived from a relapsed Philadelphia-positive acute lymphoid leukemia patient, PHA-793887 showed strong therapeutic activity also when treatment was started after establishment of high disease burden. Thus, PHA-793887 has promising therapeutic activity against acute leukemias in vitro and in vivo [1].
Clinical trial: A first in man, phase I dose-escalation study indicates that although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity. These findings shows that PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development [2].
References:
[1] Alzani R, Pedrini O, Albanese C, Ceruti R, Casolaro A, Patton V, Colotta F, Rambaldi A, Introna M, Pesenti E, Ciomei M, Golay J. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. Exp Hematol. 2010;38(4):259-269.e2.
[2] Massard C, Soria JC, Anthoney DA, Proctor A, Scaburri A, Pacciarini MA, Laffranchi B, Pellizzoni C, Kroemer G, Armand JP, Balheda R, Twelves CJ. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011;10(6):963-70.
Cas No. | 718630-59-2 | SDF | |
别名 | 3-甲基-N-[1,4,5,6-四氢-6,6-二甲基-5-[(1-甲基-4-哌啶基)甲酰基]吡咯并[3,4-C]吡唑-3-基]丁酰胺 | ||
化学名 | N-[6,6-dimethyl-5-(1-methylpiperidine-4-carbonyl)-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide | ||
Canonical SMILES | CC(C)CC(=O)NC1=NNC2=C1CN(C2(C)C)C(=O)C3CCN(CC3)C | ||
分子式 | C19H31N5O2 | 分子量 | 361.48 |
溶解度 | ≥ 18.05mg/mL in DMSO, ≥ 7.73 mg/mL in EtOH | 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 | |||
1 mg | 5 mg | 10 mg | |
1 mM | 2.7664 mL | 13.832 mL | 27.664 mL |
5 mM | 0.5533 mL | 2.7664 mL | 5.5328 mL |
10 mM | 0.2766 mL | 1.3832 mL | 2.7664 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。
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