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Bioorg Med Chem. 2014 Dec 15;22(24):6876-84. doi: 10.1016/j.bmc.2014.10.030. Epub 2014 Oct 27.

Discovery of novel Bcr-Abl inhibitors targeting myristoyl pocket and ATP site.

Author information

1
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
2
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.

Abstract

Bcr-Abl plays an essential role in the pathogenesis and development of chronic myeloid leukaemia (CML). Inhibition of Bcr-Abl has great potential for therapeutic intervention in CML. In order to obtain novel and potent Bcr-Abl inhibitors, twenty seven 4,6-disubstituted pyrimidines were synthesized and evaluated herein. The biological results indicated that four compounds of them (C4, C5, C16, and C23) were potent Bcr-Abl inhibitors which were comparable to positive control. Moreover, C4 and C5 displayed promising antiproliferative activity against K562 cells. The results suggested that these 4,6-disubstituted pyrimidines could serve as promising leads for further optimization of Bcr-Abl inhibitors.

KEYWORDS:

ATP-binding site; Allosteric pocket; Bcr–Abl; Inhibitors; Myristoyl pocket

PMID:
25464886
DOI:
10.1016/j.bmc.2014.10.030
[Indexed for MEDLINE]

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