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Details

Stereochemistry ACHIRAL
Molecular Formula C25H32N8O.C4H4O4
Molecular Weight 576.6467
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of MILCICLIB MALEATE

SMILES

OC(=O)\C=C/C(O)=O.CNC(=O)C1=NN(C)C2=C1C(C)(C)CC3=CN=C(NC4=CC=C(C=C4)N5CCN(C)CC5)N=C23

InChI

InChIKey=DGVCEXQFNYYRQI-BTJKTKAUSA-N
InChI=1S/C25H32N8O.C4H4O4/c1-25(2)14-16-15-27-24(29-20(16)22-19(25)21(23(34)26-3)30-32(22)5)28-17-6-8-18(9-7-17)33-12-10-31(4)11-13-33;5-3(6)1-2-4(7)8/h6-9,15H,10-14H2,1-5H3,(H,26,34)(H,27,28,29);1-2H,(H,5,6)(H,7,8)/b;2-1-

HIDE SMILES / InChI

Molecular Formula C4H4O4
Molecular Weight 116.0722
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Molecular Formula C25H32N8O
Molecular Weight 460.5746
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

An orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) and thropomyosin receptor kinase A (TRKA), with potential antineoplastic activity. CDK2/TRKA inhibitor PHA-848125 AC potently inhibits cyclin-dependent kinase 2 (CDK2) and exhibits activity against other CDKs including CDK1 and CDK4, in addition to TRKA. Inhibition of these kinases may result in cell cycle arrest and apoptosis of tumor cells that express these kinases. Milciclib is currently in phase II clinical trials for thymic carcinoma, glioma and liver cancer. The most common adverse events are nausea and asthenia, vomiting, myasthenic syndrome, dehydration, hypophosphatemia, cytolytic hepatitis and plantar fasciitis.

CNS Activity

Approval Year

PubMed

PubMed

TitleDatePubMed
Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.
2009 Aug 27
Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy.
2010 Aug
Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging.
2010 Mar
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.
2010 May
Patents

Sample Use Guides

In Vivo Use Guide
150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.
Route of Administration: Oral
In Vitro Use Guide
The effects of compound Milciclib on the cell cycle progression and DNA synthesis were analyzed using flow cytometry analysis and BrdU incorporation, respectively, on A2780 ovarian carcinoma cells in exponential growth in the presence or absence of compound, for 24 h at 1 μM. At this concentration, the compound was able to show a clear reduction of S phase population, which was associated with an increase of G1 population as expected for a CDK2/cyclin A inhibitor.
Substance Class Chemical
Created
by admin
on Mon Oct 21 21:00:09 UTC 2019
Edited
by admin
on Mon Oct 21 21:00:09 UTC 2019
Record UNII
82W826FL6S
Record Status Validated (UNII)
Record Version
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Name Type Language
MILCICLIB MALEATE
Common Name English
PHA-848125AC
Code English
MILCICLIB MALEATE [WHO-DD]
Common Name English
1H-PYRAZOLO(4,3-H)QUINAZOLINE-3-CARBOXAMIDE, 4,5-DIHYDRO-N,1,4,4-TETRAMETHYL-8-((4-(4-METHYL-1-PIPERAZINYL)PHENYL)AMINO)-, (2Z)-2-BUTENEDIOATE (1:1)
Systematic Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 375512
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
EU-Orphan Drug EU/3/12/1059
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
NCI_THESAURUS C129825
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
NCI_THESAURUS C2185
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
Code System Code Type Description
NCI_THESAURUS
C88312
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
PRIMARY
CAS
1253645-38-3
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
PRIMARY
PUBCHEM
46937352
Created by admin on Mon Oct 21 21:00:09 UTC 2019 , Edited by admin on Mon Oct 21 21:00:09 UTC 2019
PRIMARY
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