Saturday, October 3, 2015

Drugs in Clinical Pipeline: Bafetinib

Bafetinib [(S)-N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)benzamide] is a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor which is 25 to 55 times more potent than Imatinib mesylate in vitro and at least 10 times more potent in vivoIt is a rationally developed tyrosine kinase inhibitor based on the chemical structure of Imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, Bafetinib targets the Src family kinase Lyn, which has been associated with resistance to Imatinib in CML. Bafetinib shows potent and selective inhibitory activity against ABL (IC50 = 11 nM) and Lyn (IC50 = 26 nM) kinases. The IC50 values of Bafetinib against wild-type Bcr-Abl in human erythroleukemia K562 cells and human embryonic kidney 293T cells are 11 and 22 nM, respectively, while the corresponding values for Imatinib are 280 and 1200 nM. Bafetinib is therefore 25 to 55 times more potent than imatinib in blocking Bcr-Abl autophosphorylation [1, 2]. 

The second-generation BCR-ABL inhibitor Bafetinib is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. Researchers have performed an unbiased chemical proteomics native target profile of Bafetinib in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new Bafetinib targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of Bafetinib. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, Bafetinib does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make Bafetinib a valuable component in the drug arsenal against Chronic Myeloid Leukemia (CML) [3].

Bafetinib inhibits 12 of the 13 most frequent Imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of Bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with Imatinib-resistant or -intolerant CML have confirmed that Bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, Bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors [4].

Bafetinib is being developed by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. 

The activity of Bafetinib is as follows:

IC50 (ABL enzyme assay) = 11 nM
IC50 (LYN enzyme assay) = 26 nM
IC50 (ABL2 enzyme assay) = 9 nM
IC50 (c-KIT enzyme assay) = 840 nM
IC50 (c-KITV560G enzyme assay) = 51 nM
IC50 (PDGFRα enzyme assay) = 56 nM
IC50 (PDGFRαD842V enzyme assay) = 1281 nM
IC50 (PDGFRαV561D enzyme assay) = 59 nM

Ref 3 gives IC50 for ABL and LYN as 9 and 51 nM, respectively.

Common Name: Bafetinib
Synonyms: INNO-406; INNO406; INNO 406; NS-187; NS187; NS 187; CNS-9
IUPAC Name: (S)-N-(3-([4,5'-bipyrimidin]-2-ylamino)-4-methylphenyl)-4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)benzamide
CAS Number: 859212-16-1
Mechanism of Action: Kinase Inhibitor; Dual-Kinase Inhibitor; ABL Kinase Inhibitor; LYN Kinase Inhibitor
Indication: Various Cancers; Treatment of Chronic Myeloid Leukemia
Development Stage: Phase II
Company: CytRx Corporation/Nippon Shinyaku Co

1. Tomoko, N.; et. al. NS-187 (INNO-406), a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor. Anal Chem Insights 2007, 2, 93-106.
2. Asaki, T.; et. al. Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors. Bioorg Med Chem Lett 2006, 16(5), 1421-1425.
3. Rix, U.; et. al. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia 2010, 24(1), 44-50.
4. Santos, F. P.; et. al. Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Curr Opin Investig Drugs 2010, 11(12), 1450-1465.