MILCICLIB MALEATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C25H32N8O.C4H4O4
Molecular Weight	576.6467
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C/C(O)=O.CNC(=O)C1=NN(C)C2=C1C(C)(C)CC3=C2N=C(NC4=CC=C(C=C4)N5CCN(C)CC5)N=C3

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

Description
Sources: https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=660138
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800026196 | http://www.tizianalifesciences.com/Thymic_Liver_Cancer.html | http://meetinglibrary.asco.org/content/131226-144 | https://www.ncbi.nlm.nih.gov/pubmed/22160853

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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
CDK2/Cyclin A 7 Target ID: CHEMBL3038469 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	45.0 nM [IC50]
Cyclin-dependent kinase 4/cyclin D1 11 Target ID: CHEMBL1907601 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	160.0 nM [IC50]
Cyclin-dependent kinase 2/cyclin E 10 Target ID: CHEMBL2094126 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	363.0 nM [IC50]
Cyclin-dependent kinase 5/CDK5 activator 1 8 Target ID: CHEMBL1907600 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	265.0 nM [IC50]
Cyclin-dependent kinase 1/cyclin B 5 Target ID: CHEMBL2094127 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	398.0 nM [IC50]
Cyclin-dependent kinase 7/ cyclin H 7 Target ID: CHEMBL2111288 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	150.0 nM [IC50]
Nerve growth factor receptor Trk-A 15 Target ID: CHEMBL2815 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19603809	Inhibitor 8297	53.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Thymic carcinoma 2 Sources: http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2013/07/WC500145399.pdf	Primary	Phase II 1132	Unknown Approved Use Unknown
Glioma 21 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23347136	Primary	Phase II 1132	Unknown Approved Use Unknown
Hepatocellular carcinoma 83 Sources: http://www.tizianalifesciences.com/Thymic_Liver_Cancer.html	Primary	Phase II 1132	Unknown Approved Use Unknown

Sourcing

Vendor/Aggregator	ID	URL
AChemBlock	A-627	http://www.achemblock.com/catalogsearch/result/?q=A-627
AK Scientific	Y0330	https://aksci.com/item_detail.php?cat=Y0330
AOBIOUS INC	AOB87199	http://aobious.com/aobious/search?search_query=AOB87199
Angene	AGN-PC-0UGSGY	http://www.angenechemical.com/productshow/AGN-PC-0UGSGY.html
ApexBio Technology	A8501	https://www.apexbt.com/catalogsearch/result/?q=A8501
BLD Pharm	BD211339	http://www.bldpharm.com/search/Search.html?keyword=BD211339
BOC Sciences	802539-81-7	http://www.bocsci.com/description.asp?cas=802539-81-7
Chem Scene	CS-0579	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0579
ChemShuttle	111897	https://www.chemshuttle.com/catalogsearch/result/?q=111897
Debye Scientific	DB-075668	https://www.debyesci.com/index.php?id=product&ext[cno]=DB-075668
Excenen	EX-A2135	http://www.excenen.com/searchresultlist.php?id=EX-A2135
KeyOrganics	AS-56203	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-56203
Lab Seeker	SC-85447	http://www.labseeker.com/search.php?keywords=SC-85447&category=0
LabSeeker	SC-85447	http://www.labseeker.com/search.php?keywords=SC-85447&category=0
Matrix Scientific	147239	http://www.matrixscientific.com/147239.html
MedChem Express	HY-10424	https://www.medchemexpress.com/search.html?q=HY-10424&ft=&fa=&fp=
MolPort	MolPort-021-804-994	https://www.molport.com/shop/molecule-link/MolPort-021-804-994
Molnova	M16004	https://www.molnova.com/en/serch-list.html?keywords=M16004
MuseChem	I004922	https://www.musechem.com/product/I004922.html
ShangHai Biochempartner	BCP01918	http://www.biochempartner.com/search_BCP01918
Toronto Research Chemicals	P294490	https://www.trc-canada.com/product-detail/?CatNum=P294490
eMolecules	43366920	https://orderbb.emolecules.com/search/#?query=43366920
eNovation Chemicals	D372562	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D372562&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-5534623468	https://mcule.com/MCULE-5534623468/

PubMed

Title	Date	PubMed
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	19603809
Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy.	2010 Aug	20682657
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	20197397
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	20026273

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.

Name

Type

Language

MILCICLIB MALEATE

Common Name

English

PHA-848125AC

Code

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

Milciclib maleate [WHO-DD]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/12/1059