BCR-ABL1 tyrosine kinase (wild-type and most imatinib-resistant mutants except T315I); Radotinib (IY 5511; Supect) was confirmed to inhibit BCR-ABL1-mediated signaling in patients with BCR-ABL1+ chronic myeloid leukemia (CML) [1]

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.

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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.

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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

In a multicenter, single-arm clinical trial of patients with chronic-phase (CP) CML (n=150) who had resistance or intolerance to prior BCR-ABL1 tyrosine kinase inhibitors (TKIs, e.g., imatinib, nilotinib, dasatinib):
1. Patient baseline: Median age 48 years (range 18–77 years); 72% had resistance to prior TKIs, 28% had intolerance; 65% had received ≥2 prior TKIs.
2. Treatment regimen: Radotinib (IY 5511; Supect) was administered orally at an initial dose of 400 mg twice daily (800 mg/day). Dose adjustments (reduction to 300 mg twice daily or interruption) were allowed for grade ≥3 adverse events. Median treatment duration was 12 months (range 1–24 months).
3. Efficacy outcomes:
- Complete Hematologic Response (CHR): Achieved in 92% of patients (138/150); median time to CHR was 1 month.
- Complete Cytogenetic Response (CCyR): Achieved in 31% of patients (47/150); median time to CCyR was 3 months. Among patients with baseline cytogenetic data (n=142), 40% (57/142) achieved major cytogenetic response (MCyR, defined as 0–35% Ph+ metaphases).
- Major Molecular Response (MMR): Achieved in 22% of patients (33/150); median time to MMR was 6 months.
- Response durability: At 12 months, 85% of CHR, 78% of CCyR, and 70% of MMR were maintained.
4. Mechanism correlation: Patients achieving CCyR/MMR showed a significant reduction in BCR-ABL1 transcript levels (measured by quantitative RT-PCR) at 3–6 months, confirming Radotinib (IY 5511; Supect) inhibition of BCR-ABL1 activity in vivo [1]

Adverse Events (AEs):
1. Most common non-hematologic adverse events (all grades): nausea (45%), diarrhea (38%), fatigue (32%), rash (28%), and headache (25%). Grade ≥3 non-hematologic adverse events were rare (all <5%), and no Grade 4 events were reported.
2. Hematologic adverse events (all grades): neutropenia (35%), thrombocytopenia (28%), and anemia (18%). Grade ≥3 hematologic adverse events: neutropenia (12%), thrombocytopenia (8%), and anemia (5%); no Grade 4 hematologic toxicities were reported. 3. Organ toxicity: No significant elevations in serum ALT/AST (liver) or creatinine (kidney) were observed (≥3 grade abnormality incidence <2%), indicating no significant hepatotoxicity or nephrotoxicity. - Dosage adjustment: 22% of patients (33/150) required a dose reduction (to 300 mg twice daily) due to adverse events; 15% of patients (22/150) temporarily discontinued treatment. [1]

[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.

Radotinib is being investigated for the treatment of BCR-ABL-positive chronic myeloid leukemia. Radotinib is a second-generation tyrosine kinase inhibitor that inhibits the Bcr-Abl fusion protein and platelet-derived growth factor receptor (PDGFR), exhibiting potential antitumor activity. After administration, radiutinib specifically inhibits the Bcr-Abl fusion protein, an abnormal enzyme expressed in Philadelphia chromosome-positive chronic myeloid leukemia (CML) cells. Furthermore, the drug inhibits PDGFR, thereby blocking PDGFR-mediated signal transduction pathways. Radotinib's inhibition of these specific tyrosine kinases may reduce cell proliferation and inhibit angiogenesis. PDGFR, an upregulated receptor tyrosine kinase in various tumor cell types, is crucial for cell migration and microvascular development. Drug Indications Radotinib is indicated for the treatment of various cancers, particularly for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) who are resistant to or intolerant of other Bcr-Abl tyrosine kinase inhibitors, such as those resistant to or intolerant of imatinib. Mechanism of Action Philadelphia chromosome-positive (Ph+) leukemia is driven by the constitutive enzyme activity of the BCR-ABL1 fusion kinase. Tyrosine kinase inhibitors (TKIs) block the activity of BCR-ABL1 and have been successfully used clinically to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

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Radotinib (IY 5511; Supect) is an oral BCR-ABL1 tyrosine kinase inhibitor developed specifically for the treatment of patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant to or intolerant of first- or second-generation TKIs (such as imatinib and nilotinib). Its clinical value lies in overcoming TKI resistance mediated by most BCR-ABL1 mutations (except for the T315I "gatekeeper" mutation)[1]
- Clinical trials have demonstrated that radoltinib (IY 5511; Supect) can provide durable hematologic, cytogenetic, and molecular remissions in patients with chronic phase chronic myeloid leukemia (CP-CML) who have previously received extensive therapy, with a good safety profile (low incidence of serious adverse events and organ toxicity). This supports its role as a salvage therapy for TKI-refractory CML[1]

C27H21F3N8O

530.50

530.179

926037-48-1

Radotinib-d6;2754051-83-5

16063245

Light yellow to yellow solid powder

1.4±0.1 g/cm3

1.665

4.29

2

10

6

39

818

0

DUPWHXBITIZIKZ-UHFFFAOYSA-N

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)

4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyrazin-2-yl)pyrimidin-2-yl)amino)benzamide

IY-5511; IY5511; Radotinib; IY-5511 HCl; IY 5511; IY5511 HCl; trade name Supect.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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