Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia

Fabio P.S. Santos, Hagop Kantarjian, Jorge Cortes, Alfonso Quintas-Cardama

Research output: Contribution to journalArticle

Abstract

Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It 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. In preclinical studies, bafetinib was 25-to 55-fold more potent than imatinib in vitro and 10-fold more potent in vivo. 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.

Original languageEnglish (US)
Pages (from-to)1450-1465
Number of pages16
JournalCurrent Opinion in Investigational Drugs
Volume11
Issue number12
StatePublished - Dec 1 2010
Externally publishedYes

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bcr-abl Fusion Proteins
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Therapeutics
Protein-Tyrosine Kinases
bafetinib
Phase II Clinical Trials
Clinical Trials, Phase I
src-Family Kinases
B-Cell Chronic Lymphocytic Leukemia
Licensure
Blood-Brain Barrier
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Point Mutation
Brain Neoplasms
Cytogenetics
Prostatic Neoplasms
Phosphotransferases
Imatinib Mesylate

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. / Santos, Fabio P.S.; Kantarjian, Hagop; Cortes, Jorge; Quintas-Cardama, Alfonso.

In: Current Opinion in Investigational Drugs, Vol. 11, No. 12, 01.12.2010, p. 1450-1465.

Research output: Contribution to journalArticle

Santos, Fabio P.S. ; Kantarjian, Hagop ; Cortes, Jorge ; Quintas-Cardama, Alfonso. / Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. In: Current Opinion in Investigational Drugs. 2010 ; Vol. 11, No. 12. pp. 1450-1465.
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