Milciclib | PHA-848125 | CAS#802539-81-7 | CAS#802540-32-5

MedKoo Cat#: 202233 | Name: Milciclib

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Milciclib, also known as PHA-848125 or PHA-848125AC, is 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. CDKs are serine/threonine kinases involved in regulation of the cell cycle and may be overexpressed in some cancer cell types.

Chemical Structure

Milciclib

CAS#802539-81-7

Theoretical Analysis

MedKoo Cat#: 202233

Name: Milciclib

CAS#: 802539-81-7

Chemical Formula: C25H32N8O

Exact Mass: 460.2699

Molecular Weight: 460.59

Elemental Analysis: C, 65.19; H, 7.00; N, 24.33; O, 3.47

Price and Availability

Size	Price	Availability
10mg	USD 350.00	2 Weeks
25mg	USD 650.00	2 Weeks
50mg	USD 950.00	2 Weeks

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Synonym

PHA-848125; PHA848125; PHA 848125; PHA-848125AC; PHA 848125AC; PHA848125AC; Milciclib.

IUPAC/Chemical Name

N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide

InChi Key

RXZMYLDMFYNEIM-UHFFFAOYSA-N

InChi Code

InChI=1S/C25H32N8O/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/h6-9,15H,10-14H2,1-5H3,(H,26,34)(H,27,28,29)

SMILES Code

O=C(C1=NN(C)C2=C1C(C)(C)CC3=CN=C(NC4=CC=C(N5CCN(C)CC5)C=C4)N=C23)NC

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Milciclib (PHA-848125) is a spectrum selective multi-kinase inhibitor of cyclin-dependent kinases initially identified in a CDK2 inhibitor project, as a potent inhibitor of the CDK2/Cyclin A complex. It possesses an unusual kinase inhibitory profile, being active also against other selected members of receptors tyrosine kinases, src family and splicing kinases. Uncontrolled cell proliferation is a hallmark of cancer cells. Alterations of the expression and/or genetic mutations of Cdks and other components of the pRB pathway, controlling the correct entry and progression through the cell cycle, were reported in more than 90% of human neoplasms. Milciclib is currently in phase II as single agent in thymic carcinoma. (source: http://www.nervianoms.com/en/oncology-en/pipeline/milciclib.html).

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Milciclib (PHA-848125) is a potent, ATP-competitive and 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.

In vitro activity:

In this study, gene expression profiling showed that PHA-848125 significantly modulated the expression of 128 genes, predominantly involved in cell cycle control, in the highly drug-sensitive GL-Mel (p53 wild-type) melanoma cells. Upon PHA-848125 treatment, a marked PTTG1 down-modulation was also observed in A375 cells (p53 wild-type) but not in CN-Mel cells (p53 mutated). Reference: Biochem Pharmacol. 2012 Sep 1;84(5):598-611. https://pubmed.ncbi.nlm.nih.gov/22704958/

In vivo activity:

Treatment of K-Ras(G12D)LA2 mice with 40 mg/kg twice daily for 10 days with PHA-848125 induced a significant tumor growth inhibition at the end of treatment (P < 0.005) and this was accompanied by a reduction in the cell membrane turnover, as seen by 11C-Choline-positron emission tomography (P < 0.05). Reference: Mol Cancer Ther. 2010 Mar;9(3):673-81. https://pubmed.ncbi.nlm.nih.gov/20197397/

	Solvent	mg/mL	mM
Solubility
	DMF	5.0	10.86
	DMSO	15.7	34.01
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.09

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 460.59 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Albanese C, Alzani R, Amboldi N, Degrassi A, Festuccia C, Fiorentini F, Gravina G, Mercurio C, Pastori W, Brasca M, Pesenti E, Galvani A, Ciomei M. Anti-tumour efficacy on glioma models of PHA-848125, a multi-kinase inhibitor able to cross the blood-brain barrier. Br J Pharmacol. 2013 May;169(1):156-66. doi: 10.1111/bph.12112. PMID: 23347136; PMCID: PMC3632246. 2. 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. 3. 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. 4. Degrassi A, Russo M, Nanni C, Patton V, Alzani R, Giusti AM, Fanti S, Ciomei M, Pesenti E, Texido G. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol Cancer Ther. 2010 Mar;9(3):673-81. doi: 10.1158/1535-7163.MCT-09-0726. Epub 2010 Mar 2. PMID: 20197397.

In vitro protocol:

In vivo protocol:

1. 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. 2. Degrassi A, Russo M, Nanni C, Patton V, Alzani R, Giusti AM, Fanti S, Ciomei M, Pesenti E, Texido G. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol Cancer Ther. 2010 Mar;9(3):673-81. doi: 10.1158/1535-7163.MCT-09-0726. Epub 2010 Mar 2. PMID: 20197397.

1: Degrassi A, Russo M, Nanni C, Patton V, Alzani R, Giusti AM, Fanti S, Ciomei M, Pesenti E, Texido G. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol Cancer Ther. 2010 Mar;9(3):673-81. Epub 2010 Mar 2. PubMed PMID: 20197397. 2: Caporali S, Alvino E, Starace G, Ciomei M, Brasca MG, Levati L, Garbin A, Castiglia D, Covaciu C, Bonmassar E, D'Atri S. 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. Epub 2009 Dec 21. PubMed PMID: 20026273. 3: Brasca MG, Amboldi N, Ballinari D, Cameron A, Casale E, Cervi G, Colombo M, Colotta F, Croci V, D'Alessio R, Fiorentini F, Isacchi A, Mercurio C, Moretti W, Panzeri A, Pastori W, Pevarello P, Quartieri F, Roletto F, Traquandi G, Vianello P, Vulpetti A, Ciomei M. 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 Jul 15. [Epub ahead of print] PubMed PMID: 19603809. 4: Tomillero A, Moral MA. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2009 Apr;31(3):183-226. PubMed PMID: 19536362.