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Chemical Structure| 802539-81-7 同义名 : PHA-848125
CAS号 : 802539-81-7
货号 : A127625
分子式 : C25H32N8O
纯度 : 99%+
分子量 : 460.575
MDL号 : MFCD17169990
存储条件：

Pure form Keep in dark place,Sealed in dry,Store in freezer, under -20°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 18 mg/mL(39.08 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

30% propylene glycol+5% Tween 80+65% water 30 mg/mL suspension

生物活性
靶点

  • CDK5

    CDK5/p35, IC50:265 nM

  • CDK4

    CDK4/CyclinD1, IC50:160 nM

  • CDK2

    CDK2/CyclinE, IC50:363 nM

    CDK2/CyclinA, IC50:45 nM

  • CDK7

    CDK7/CyclinH, IC50:150 nM

  • CDK1

    CDK1/CyclinB, IC50:398 nM
描述 Cyclin-dependent kinases (CDKs) are a family of protein kinases which along with their regulatory subunit cyclins play a key role in the growth, development, proliferation and death of eukaryotic cells and are responsible for insuring integrity in the coordination of events through the cell cycle [3]. PHA-848125 is a potent, dual inhibitor of CDK and Tropomyosin receptor kinase (TRK), with IC50s of 45, 150, 160, 363, 398 nM and 53 nM for cyclin A/CDK2, cyclin H/CDK7, cyclin D1/CDK4, cyclin E/CDK2, cyclin B/CDK1 and TRKA, respectively [4]. PHA-848125 (0.156 or 0.625 μM) up-regulates the expression of PDCD4, DDIT4, SESN2/sestrin 2 and DEPDC6/DEPTOR in GL-Mel cells [4]. PHA-848125 induces a clear accumulation of cells in G1 phase and it strongly inhibits NGF (nerve growth factor)-induced phosphorylation of TRKA (tropomyosin receptor kinase) in a dose-dependent manner [5]. PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. PHA-848125 (5, 10, and 15 mg/kg, p.o.) inhibits the growth of tumor in 7, 12-dimethylbenz anthracene (DMBA)-induced rat mammary carcinoma model [5].
作用机制 PHA-848125 is a potent, ATP-competitive CDK inhibitor for CDK2 with IC50 of 45 nM, being > 3-fold selective for CDK2 than CDK1, 2, 4, 5, and 7.
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human A2780 cells Proliferation assay 72 h Antiproliferative activity against human A2780 cells after 72 hrs by cell Titer_Glo assay, IC50=0.2 μM 19603809
human A2780 cells Function assay Inhibition of CDK2 in human A2780 cells assessed as reduction of hyperphosphorylated form of retinoblastoma protein at 1 uM relative to control 19603809
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT03109886 Hepatocellular Carcinoma Phase 2 Active, not recruiting August 2019 Greece ... 展开 >> Ippokrateio General Hospital of Athens Athens, Greece, 11527 Laiko General Hospital of Athens Athens, Greece, 11527 General University Hospital of Larissa Larissa, Greece, 41110 University General Hospital of Thessaloniki - AHEPA Thessaloniki, Greece, 54636 Israel Rambam Health Corporation Haifa, Israel, 31096 Rabin Medical Center - Beilinson Hospital Petah Tikva, Israel, 4941492 The Sheba Academic Medical Center Hospital - Tel Hashomer Ramat Gan, Israel Tel Aviv Sourasky Medical Center Tel Aviv, Israel, 64239 Italy Istituto Clinico Humanitas Rozzano, MI, Italy, 20089 AOU S. Orsola Malpighi Bologna Bologna, Italy, 40138 Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano, Italy, 20122 Azienda Ospedaliera Universitaria Policlinico di Modena Modena, Italy, 41124 A.O.U. Federico II Napoli, Italy, 80131 A.O. U. Policlinico Paolo Giaccone Palermo, Italy, 90127 收起 <<
NCT01011439 Thymic Carcinoma Phase 2 Active, not recruiting December 2018 United States, Arizona ... 展开 >> TGen Clinical Research Services at Scottsdale Healthcare Scottsdale, Arizona, United States, 85258 United States, Maryland NIH, Center for Cancer Research, Medical Oncology Bethesda, Maryland, United States, 20892 France Hopital Larrey Toulouse Cedex, France, 31059 Institut de cancerologie Gustave Roussy Villejuif Cedex, France, 94805 Italy Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milano, (mi), Italy, 20133 Azienda Ospedaliera San Luigi Gonzaga Orbassano, Italy, 10043 收起 <<
NCT01301391 - Active, not recruiting - -
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.17mL

0.43mL

0.22mL

10.86mL

2.17mL

1.09mL

21.71mL

4.34mL

2.17mL
参考文献

[1]Caporali S, Alvino E, et al. The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound. Pharmacol Res. 2010 May;61(5):437-48.

[2]Brasca MG, Amboldi N, et al. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl] amino}-4,5-dihydro-1H-py razolo[4,3-h] quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem. 2009 Aug 27;52(16):5152-63.

[3]Misra RN, Xiao Hy, Rawlins DB, Shan W, Kellar KA, Mulheron JG, Sack JS, Tokarski JS, Kimball SD, Webster KR. 1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2,6-Difluorophenacyl analogues. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2405-8. doi: 10.1016/s0960-894x(03)00381-0. PMID: 12824044.

[4]Caporali S, Alvino E, Levati L, Esposito AI, Ciomei M, Brasca MG, Del Bufalo D, Desideri M, Bonmassar E, Pfeffer U, D'Atri S. Down-regulation of the PTTG1 proto-oncogene contributes to the melanoma suppressive effects of the cyclin-dependent kinase inhibitor PHA-848125. Biochem Pharmacol. 2012 Sep 1;84(5):598-611. doi: 10.1016/j.bcp.2012.06.004. Epub 2012 Jun 13. PMID: 22704958.

[5]Albanese C, Alzani R, Amboldi N, Avanzi N, Ballinari D, Brasca MG, Festuccia C, Fiorentini F, Locatelli G, Pastori W, Patton V, Roletto F, Colotta F, Galvani A, Isacchi A, Moll J, Pesenti E, Mercurio C, Ciomei M. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol Cancer Ther. 2010 Aug;9(8):2243-54. doi: 10.1158/1535-7163.MCT-10-0190. Epub 2010 Aug 3. PMID: 20682657.