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Chemical Structure| 802539-81-7 Chemical Structure| 802539-81-7

Structure of Milciclib
CAS No.: 802539-81-7

Chemical Structure| 802539-81-7

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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.

Synonyms: PHA-848125

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Product Details of Milciclib

CAS No. :802539-81-7
Formula : C25H32N8O
M.W : 460.57
SMILES Code : O=C(NC)C1=NN(C2=C1C(C)(CC3=CN=C(N=C23)NC4=CC=C(C=C4)N5CCN(CC5)C)C)C
Synonyms :
PHA-848125
MDL No. :MFCD17169990
InChI Key :RXZMYLDMFYNEIM-UHFFFAOYSA-N
Pubchem ID :16718576

Safety of Milciclib

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Related Pathways of Milciclib

Hedgehog

Isoform Comparison

Biological Activity

Target
  • 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

In Vitro:

Cell Line
Concentration Treated Time Description References
SKOV3ip1 1 µM 16 hours Milciclib inhibited adhesion, invasion, and proliferation of SKOV3ip1 cells. Mol Cancer Ther. 2020 Jan;19(1):52-62.
Tyk-nu 1 µM 16 hours Milciclib inhibited adhesion, invasion, and proliferation of Tyk-nu cells. Mol Cancer Ther. 2020 Jan;19(1):52-62.
H460 cells 10 µM 24 hours Milciclib blocks glucose consumption in H460 cells by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Nat Commun. 2019 Nov 29;10(1):5444.
H1975 cells 10 µM 24 hours Milciclib reduces glucose consumption in H1975 cells by inhibiting CDK7. Nat Commun. 2019 Nov 29;10(1):5444.
SF539 1.4 µM 24 hours Inhibition of cell proliferation, reduction of DNA synthesis, induction of autophagy Br J Pharmacol. 2013 May;169(1):156-66.
SF268 2.5 µM 24 hours Inhibition of cell proliferation, reduction of DNA synthesis, induction of autophagy Br J Pharmacol. 2013 May;169(1):156-66.
U251 2.1 µM 24 hours Inhibition of cell proliferation, reduction of DNA synthesis, induction of autophagy Br J Pharmacol. 2013 May;169(1):156-66.
U87MG 1.6 µM 24 hours Inhibition of cell proliferation, reduction of DNA synthesis, induction of autophagy Br J Pharmacol. 2013 May;169(1):156-66.

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
BALB/c Nude mice Transplanted tumor model Oral 20 mg/kg Once daily for 40 days Evaluate the inhibitory effect of PHA-848125 on transplanted tumors Am J Cancer Res. 2024 May 15;14(5):2157-2171
Mice H460 cell xenografts Oral 30 mg/kg Twice daily, 24 hours Milciclib selectively reduces glucose consumption in H460 cell xenografts by inhibiting CDK7, without affecting glucose consumption in the mouse brain, heart, liver, or muscle. Nat Commun. 2019 Nov 29;10(1):5444.
BALB/c athymic nu/nu male U87MG and U251 subcutaneous xenograft models Oral 40 mg/kg Twice daily for 10 days Evaluate the anti-tumor efficacy of PHA-848125 in subcutaneous xenograft models, observed tumor growth inhibition Br J Pharmacol. 2013 May;169(1):156-66.
C57BL/6NCrl mice ID8p53−/− Intraperitoneal injection 5mg/kg/day Daily for 10 days Milciclib significantly reduced omental tumor growth and prolonged survival in mice. Mol Cancer Ther. 2020 Jan;19(1):52-62.

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT03109886 Hepatocellular Carcinoma Phase 2 Active, not recruiting August 2019 Greece ... More >> 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 Less <<
NCT01011439 Thymic Carcinoma Phase 2 Active, not recruiting December 2018 United States, Arizona ... More >> 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 Less <<
NCT01301391 - Active, not recruiting - -
NCT01301391 Malignant Thymoma Phase 2 Active, not recruiting December 2018 United States, District of Col... More >>umbia MedStar Georgetown University Hospital Washington, District of Columbia, United States, 20007 United States, Maryland NIH, Center for Cancer Research, Medical Oncology Bethesda, Maryland, United States, 20892 Italy Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milano, (mi), Italy, 20133 Less <<
NCT01011439 - Active, not recruiting - -
NCT01300468 Solid Tumour Phase 1 Completed - United States, Arizona ... More >> Scottsdale Clinical Research Institute Scottsdale, Arizona, United States, 85258 United States, Maryland The Johns Hopkins University Baltiomore, Maryland, United States, 21212 Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 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

References

[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.

 

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