Thursday, April 21, 2016

Radotinib | BCR-ABL1 Kinase Inhibitor | Treatment for Chronic Myeloid Leukemia I Cancer Drug

Radotinib [4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)-benzamide] is an orally available, small-molecule BCR-ABL1 tyrosine kinase inhibitor (TKI). In med-chem terminology, Radotinib and Nilotinib are structural homologues.

Radotinib: 2D and 3D Structure

In vitro, Radotinib binds BCR-ABL1 and reduces phosphorylation of CrkL, a BCR-ABL1 target protein. Furthermore, pre-clinical studies demonstrated superiority of radotinib to imatinib in both wild-type and mutant BCR-ABL1 positive CML cell lines. In a Phase I clinical trial, no dose-limiting toxicities were observed with a dose of up to 1000 mg/day.

Radotinib was noticed globally following result from a study that was designed to evaluate its efficacy and safety in patients with chronic phase-CML after resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Based on the analysis of the primary end point, a cumulative 75% of patients achieved major cytogenic response (MCyR) by 12 months. Additionally, 47% of patients achieved complete cytogenetic response (CCyR), and 22% of patients with MCyR also achieved major molecular response (MMR). OS and PFS rates at 12 months were 96.1% and 86.3%, respectively, and 9 (11.7%) patients experienced disease progression during treatment at a median follow up of 23.4 months. In the current study, 5 of 12 (42%) patients having base-line BCR-ABL1 mutations had less sensitive mutation to Nilotinib or Dasatinib. Among them, 2 patients achieved MCyR, and PFS was higher in patients with no base-line BCR-ABL1 mutations.

Radotinib as Kinase Inhibitor:
Radotinib is a BCR-ABL1 specific 2nd-generation tyrosine kinase inhibitor. In in vitro kinase assays, the IC50 value for radotinib against wild-type BCR-ABL1 kinase was 34 nM, which is relatively lower compared with the IC50 levels of c-kit (1324 nM), PDGFR (PDGFR = 75.5 nM; PDGFR-β = 130 nM) and Src (greater than 2 uM). Also, Radotinib effectively inhibited the proliferation of common mutant clones of BCR-ABL1, with the exception of T315I. In an off-target kinase assay to assess safety, DDR, EPHB, LYN, and PDGFR kinases were inhibited below the 180 nM levels.

Dosages and Approvals:
Radotinib has been approved by the KFDA (Korea Food and Drug Administration) for the treatment of patients with Philadelphia chromosome- positive chronic myeloid leukemia (CML) who have become resistant to existing drugs such as Gleevec, Tasigna and Sprycel. Supect is available as capsule for oral use, containing 100 mg or 200 mg of free Radotinib. The recommended dose is 400 mg twice daily.
Originally developed by IL-YANG pharmaceuticals of South Korea as an oral second-generation tyrosine kinase inhibitor, the drug inhibits both Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR). It is co-marketed by Daewoong Pharmaceutical Co. Ltd, in South Korea.

Radotinib Synthesis

WO2007018325A1: The patent lists synthesis and activity for various ABL1 kinase inhibitors. Radotinib is the molecule in Example 8. Synthesis for various intermediates is also provided in the patent.

Intermediate 1:

Intermediate 2:

Intermediate 3:

Final Synthesis:

WO2010018895A1: It is a modification on the above reported scheme. Diethylcyano phosphate is replaced in the last step with cheaper t-BuOK. It appears to be industrial process.


1H NMR (Estimated) for Radotinib
Experimental: 1H-NMR(DMSOd6, δ) = 2.19(s, 3H), 2.36(s, 3H), 7.24(s, 1H), 7.35(m, 2H), 7.47 (s, 1H), 7.64(d, 1H), 7.71(d, 1H), 7.92(d, 1H), 8.01(s, 1H), 8.11(s, 1H), 8.30(s, 2H), 8.47(d, 1H), 9.00(s, 1H), 10.49(s, 1H).

The most common hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%). The most common drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), nausea (2.6%), myalgia (1.3%), rash (1.3%), and pruritus (1.3%).
The most common biochemistry abnormality was hyperbilirubinemia ( 23.4%), and 12 of 18 cases were managed with dose modification. Hyperbilirubinemia generally occurred in the early period of treatment and was managed by dose reduction or transient interruption; however, 6 patients permanently discontinued treatment due to hyperbilirubinemia.
Overall elevations of alanine transaminase (ALT) and aspartate transaminase (AST) were observed in 85.7% and 72.7% of patients, respectively. Hyperglycemia was observed in 68.8% of patients, including 19.5% of patients with grade 3/4 hyperglycemia. One (1.3%) patient developed diabetes during the study, but it was not considered drug-related; 8 (10.4%) patients had a history of diabetes at baseline. However, no patients with diabetes interrupted or discontinued study drug due to aggravation of hyperglycemia or required an increase in treatment for their diabetes. Lipase elevation was observed in 37.7% of patients, including 10.4% of patients with grade 3/4 lipase elevation.

Adverse events were generally transient and managed by dose reduction or interruption. Overall adverse events were somewhat different than with other BCR-ABL1 tyrosine kinase inhibitors. For example, the incidence of hematologic adverse events was lower and the incidence of hyperbilirubinemia was higher with radotinib compared with other 2nd-generation BCR-ABL1 tyrosine kinase inhibitors.

1. Kim, D. -K.; et. al. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica 2014, 99(7), 1191-1196. (free copy)
2. Kim, D. -K.; et. al. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof. WO2007018325A1
3. Kim, D. -K.; et. al. Process for the preparation of n-phenyl-2-pyrimidine-amine derivatives. WO2010018895A1