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Eur J Med Chem. 2015 Nov 2;104:139-47. doi: 10.1016/j.ejmech.2015.09.034. Epub 2015 Oct 8.

Expanding the structural diversity of Bcr-Abl inhibitors: Dibenzoylpiperazin incorporated with 1H-indazol-3-amine.

Author information

1
Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
2
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China.
3
School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.
4
Department of Pharmacy, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, PR China. Electronic address: wangmy28@126.com.

Abstract

A series of N,N'-dibenzoylpiperazine derivatives incorporated with 1H-indazol-3-amine have been designed, synthesized and evaluated as novel Bcr-Abl inhibitors. Several title compounds exhibited potent inhibitory activity against Bcr-Abl wild type as well as T315I mutant. Two compounds, 11a and 12c, strongly suppressed the activity of native and mutant Bcr-Abl. In particular, 11a exhibited comparable potency with that of Imatinib. It potently inhibited both Bcr-Abl(WT) and Bcr-Abl(T315I) with IC50 values of 0.014 μM and 0.45 μM, respectively. Furthermore, compound 11a also inhibited the proliferation of K562 leukemia cancer cells. Therefore, it could serve as promising lead compound for further optimization of Bcr-Abl(WT) and Bcr-Abl(T315I) inhibitors.

KEYWORDS:

ATP-Binding site; Bcr-Abl; Flexible linker; Hinge-binding fragment; Resistance

PMID:
26451772
DOI:
10.1016/j.ejmech.2015.09.034
[Indexed for MEDLINE]

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