MILCICLIB MALEATE

Investigational

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

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

Molecular Formula	C4H4O4
Molecular Weight	116.0722
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Molecular Formula	C25H32N8O
Molecular Weight	460.5746
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
CDK2/Cyclin A 7	Inhibitor 8,297	45.0 nM [IC50]
Cyclin-dependent kinase 4/cyclin D1 11	Inhibitor 8,297	160.0 nM [IC50]
Cyclin-dependent kinase 2/cyclin E 10	Inhibitor 8,297	363.0 nM [IC50]
Cyclin-dependent kinase 5/CDK5 activator 1 8	Inhibitor 8,297	265.0 nM [IC50]
Cyclin-dependent kinase 1/cyclin B 5	Inhibitor 8,297	398.0 nM [IC50]
Cyclin-dependent kinase 7/ cyclin H 7	Inhibitor 8,297	150.0 nM [IC50]
Nerve growth factor receptor Trk-A 15	Inhibitor 8,297	53.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Thymic carcinoma 2	Primary	Phase II 1,132	Unknown
Glioma 21	Primary	Phase II 1,132	Unknown
Hepatocellular carcinoma 83	Primary	Phase II 1,132	Unknown

Sourcing

Sourcing

Show entries

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

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PubMed

Show entries

Title	Date	PubMed
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

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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.