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Bafetinib (NS-187, INNO-406) is an orally-available, ATP-competitive inhibitor of Bcr-Abl and Lyn with IC50

values of 11 and 26 nM, respectively. Structurally similar to imatinib, Bafetinib possesses 10- to 50-fold

greater biochemical potency as well as in cell proliferation assays (11 nM and 22 nM in K562 cells and 293T

cells, respectively). [1] In a number of point-mutated Abl kinase domains, with the exception of T315I,

Bafetinib inhibited phosphorylation much more potently than did imatinib.

Bafetinib inhibits the kinase activity of both phosphorylated and unphosphorylated Tyr393 forms of Abl with

IC50 values of 72 and 30 nM, respecitively. [1] Though Bafetinib is a pGP substrate, residual concentrations

are sufficient for anti-leukemic activity and is further aided by treatment with cyclosporin A. [2]

Bafetinib has been shown to induce cell death in Bcr-Abl leukemia cell lines by both caspase-mediated and

caspase-independent mechanisms. In vivo, this cell death is independent of the activity status of caspase. [3]

References

1.Niwa et al., NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal. Chem. Insights, 2007, 2,

   93-106. Pubmed ID: 19662183   

2. Yokota et al., INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of

   Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood,

   2007, 109(1), 306-314. Pubmed ID: 16954504   

3. Kamitsuji et al., The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell

   death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008, 15, 1712-1722.

   Pubmed ID: 18617896   

NVP-BGT226 is a novel orally bioavailable dual PI3K/mTOR inhibitor. It selectively inhibits PI3K and both

mTOR complexes mTORC1 and mTORC2, resulting in nearly complete phosphorylation-inhibition of P70S6

and 4E-BP1.

BGT226 demonstrated excellent cellular activities in inhibiting proliferations (IC50: 7-30 nM) of many tested

cell lines. Notably, cells that express PIK3CA mutation H1047R are still sensitive to the growth-inhibition of

BGT226. Flow cytometric analysis shows accumulation of cells in the G0-G1 phase with concomitant loss in

the S-phase. BGT226 induces apoptosis or autophagy of some cancer cells at IC50 less than 25nM. In

animal models, BGT226 significantly delays/inhibits tumor growth in a dose-dependent manner. BGT-226

represents a potential candidate for cancer therapy. It has entered phaseI/II clinical trials for treatment of

advanced solid tumors (including breast cancer) [1-4].

References

1. Badura S, et al. Poster Abstracts. Differential Suppressive Effects of Selective PI3K and mTOR and Dual

   PI3K/mTORC1/C2 Inhibition on Long-Term Cultured Primary Human Acute Lymphoblastic Leukemia (ALL)

   Cells Implicate a Distinct Role of mTORC2 https://ash.confex.com/ash/2010/webprogram/Paper33127.html

2. Chang KY, et al. Novel phosphoinositide 3-kinase/mTOR dual inhibitor, NVP-BGT226, displays potent

   growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo. Clin Cancer Res.

   2011. 17(22):7116-26. Pubmed ID: 21976531

3. Baumann P, et al. Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in

   multiple myeloma. Anticancer Drugs. 2012. 23(1):131-8. Pubmed ID: 21959532

4. http://clinicaltrials.gov/ct2/show/NCT00600275