Radotinib (IY 5511; Supect) 926037-48-1_Bcr-Abl_Angiogenesis_Signaling Pathways_Products

Radotinib (formerly IY-5511; IY5511; trade name Supect) is a novel, potent, selective, orally bioavailable, and 2nd generation BCR-ABL1 tyrosine kinase inhibitor with potential antineoplastic activity. It inhibits BCR-ABL1 with an IC50 of 34 nM. It was developed by Ilyang Pharmaceutical in S. Korea and has the potential for the treatment of Chronic Myeloid Leukemia.

Physicochemical Properties

Molecular Formula	C27H21F3N8O
Molecular Weight	530.50
Exact Mass	530.179
CAS #	926037-48-1
Related CAS #	Radotinib-d6;2754051-83-5
PubChem CID	16063245
Appearance	Light yellow to yellow solid powder
Density	1.4±0.1 g/cm3
Index of Refraction	1.665
LogP	4.29
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	6
Heavy Atom Count	39
Complexity	818
Defined Atom Stereocenter Count	0
InChi Key	DUPWHXBITIZIKZ-UHFFFAOYSA-N
InChi Code	InChI=1S/C27H21F3N8O/c1-16-3-4-18(9-23(16)37-26-33-6-5-22(36-26)24-13-31-7-8-32-24)25(39)35-20-10-19(27(28,29)30)11-21(12-20)38-14-17(2)34-15-38/h3-15H,1-2H3,(H,35,39)(H,33,36,37)
Chemical Name	4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyrazin-2-yl)pyrimidin-2-yl)amino)benzamide
Synonyms	IY-5511; IY5511; Radotinib; IY-5511 HCl; IY 5511; IY5511 HCl; trade name Supect.
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro

In vitro activity: In vitro, Radotinib binds BCR-ABL1 and reduces phosphorylation of CrkL, a BCR-ABL1 target protein. Radotinib also effectively inhibits the proliferation of common mutant clones of BCR-ABL1, with the exception of T315I. In AML cells, radotinib significantly decreases the cell viability, promotes differentiation, and induces CD11b expression and apoptosis. In NB4, THP-1, and Kasumi-1 cells, radotinib also induces CD11b expression, and decreases the viability.

Kinase Assay: Radotinib (formerly also known as IY-5511) is a novel, potent, selective, orally bioavailable, and second-generation BCR-ABL1 tyrosine kinase inhibitor with IC50 of 34 nM.

Cell Assay: Cells (BMCs of AML and CML patients, NB4, HL60, KASUMI-1, and THP-1 cells) are seeded in 96-well plates at a density of 2×104 cells/ml with 100 μL of medium per well and then incubated with various concentrations of radotinib (0, 1, 10, and 100 μM) for 72 h at 37°C. The CellTiter 96 solution (20 μL) is added directly to each well and plates are incubated for 4 h in a humidified 5% CO2 atmosphere at 37°C. Absorbance is measured with a PowerWave XS2 Microplate Spectrophotometer at 490 nm and the results are expressed as percentage changes from the basal condition using four to five culture wells for each experimental treatment. In some experiments, HL60 cells are cultured with 100 nM ATRA and 1 μM dasatinib for 4 days, and 10 μM radotinib is added to each group according to the planned schedule

ln Vivo

Animal Protocol

References

[1]. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica. 2014 Jul;99(7):1191-6.

Additional Infomation

Radotinib is under investigation for the treatment of Leukemia, Myelogenous, Chronic, BCR-ABL Positive.
Radotinib is a second-generation tyrosine kinase inhibitor of Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR), with potential antineoplastic activity. Upon administration, radotinib specifically inhibits the Bcr-Abl fusion protein, an abnormal enzyme expressed in Philadelphia chromosome positive chronic myeloid leukemia (CML) cells. In addition, this agent also inhibits PDGFR thereby blocking PDGFR-mediated signal transduction pathways. The inhibitory effect of radotinib on these specific tyrosine kinases may decrease cellular proliferation and inhibit angiogenesis. PDGFR, upregulated in many tumor cell types, is a receptor tyrosine kinase essential to cell migration and the development of the microvasculature.

Drug Indication
Radotinib is indicated for the treatment of different types of cancer, most notably Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) with resistance or intolerance of other Bcr-Abl tyrosine-kinase inhibitors, such as patients resistant or intolerant to imatinib.

Mechanism of Action
Philadelphia chromosome positive (Ph+) leukemia is driven by the constitutive enzymatic activity of the BCR-ABL1 fusion kinase. Tyrosine kinase inhibitors (TKIs) that block the activity of BCR-ABL1 are successfully used clinically to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (188.5 mM)

Water:<1 mg/mL

Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 0.62 mg/mL (1.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 0.62 mg/mL (1.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.8850 mL	9.4251 mL	18.8501 mL
	5 mM	0.3770 mL	1.8850 mL	3.7700 mL
	10 mM	0.1885 mL	0.9425 mL	1.8850 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

Radotinib (IY 5511; Supect) 926037-48-1

CAS No.: 926037-48-1

Physicochemical Properties

Biological Activity

Solubility Data