Virtual screening, SAR, and discovery of 5-(indole-3-yl)-2-[(2-nitrophenyl)amino] [1,3,4]-oxadiazole as a novel Bcl-2 inhibitor

被引：37

作者：

Ziedan, Noha I. ^{[1
,2
]}

Hamdy, Rania ^{[1
,2
]}

Cavaliere, Alessandra ^{[1
]}

Kourti, Malamati ^{[1
,3
]}

Prencipe, Filippo ^{[1
]}

Brancale, Andrea ^{[1
]}

Jones, Arwyn T. ^{[1
]}

Westwell, Andrew D. ^{[1
]}

机构：

[1] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff, S Glam, Wales

[2] Zagazig Univ, Fac Pharm, Zagazig, Egypt

[3] Cardiff Univ, Cardiff China Med Res Collaborat, Cardiff, S Glam, Wales

来源：

CHEMICAL BIOLOGY & DRUG DESIGN | 2017年 / 90卷 / 01期

关键词：

anti-cancer; BCl-2; inhibitor; drug design; SAR; virtual screening; SMALL-MOLECULE INHIBITORS; BREAST-CANCER CELLS; APOPTOSIS; RESISTANCE; POTENT; DOMAIN;

D O I：

10.1111/cbdd.12936

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small-molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with submicromolar IC50 values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by an enzyme-linked immunosorbent assay (IC50 = 4.27 mu m). Compound 16j has a great potential to develop into highly active anticancer agent.

引用

页码：147 / 155

页数：9

共 20 条

[1] Studies leading to potent, dual inhibitors of bcl-2 and Bcl-xL [J].

Bruncko, Milan ;

Oost, Thorsten K. ;

Belli, Barbara A. ;

Ding, Hong ;

Joseph, Mary K. ;

Kunzer, Aaron ;

Martineau, Darlene ;

McClellan, William J. ;

Mitten, Michael ;

ng, Shi-Chu Ng ;

Nimmer, Paul M. ;

Oltersdorf, Tilman ;

Park, Cheol-Min ;

Petros, Andrew M. ;

Shoemaker, Alexander R. ;

Song, Xiaohong ;

Wang, Xilu ;

Wendt, Michael D. ;

Zhang, Haichao ;

Fesik, Stephen W. ;

Rosenberg, Saul H. ;

Elmore, Steven W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (04) :641-662

[2]

CCG Inc, 2010, MOL OP ENV MOE

[3] Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL [J].

Degterev, A ;

Lugovskoy, A ;

Cardone, M ;

Mulley, B ;

Wagner, G ;

Mitchison, T ;

Yuan, JY .

NATURE CELL BIOLOGY, 2001, 3 (02) :173-182

[4] Expression of Bcl-2 in human epithelial tumor (HeLa) cells enhances clonogenic survival following exposure to 5-fluoro-2′-deoxyuridine or staurosporine, but not following exposure to etoposide or doxorubicin [J].

Elliott, MJ ;

Stribinskiene, L ;

Lock, RB .

CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1998, 41 (06) :457-463

[5] Discovery of small-molecule inhibitors of bcl-2 through structure-based computer screening [J].

Enyedy, IJ ;

Ling, Y ;

Nacro, K ;

Tomita, Y ;

Wu, XH ;

Cao, YY ;

Guo, RB ;

Li, BH ;

Zhu, XF ;

Huang, Y ;

Long, YQ ;

Roller, PP ;

Yang, DJ ;

Wang, SM .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (25) :4313-4324

[6] The Bcl-2 Homology Domain 3 Mimetic Gossypol Induces Both Beclin 1-dependent and Beclin 1-independent Cytoprotective Autophagy in Cancer Cells [J].

Gao, Ping ;

Bauvy, Chantal ;

Souquere, Sylvie ;

Tonelli, Giovanni ;

Liu, Lei ;

Zhu, Yushan ;

Qiao, Zhenzhen ;

Bakula, Daniela ;

Proikas-Cezanne, Tassula ;

Pierron, Gerard ;

Codogno, Patrice ;

Chen, Quan ;

Mehrpour, Maryam .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (33) :25570-25581

[7] Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents [J].

Hamdy, Rania ;

Ziedan, Noha ;

Ali, Samia ;

El-Sadek, Mohamed ;

Lashin, Elsaid ;

Brancale, Andrea ;

Jones, Arwyn T. ;

Westwell, Andrew D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (08) :2391-2394

[8] Hallmarks of Cancer: The Next Generation [J].

Hanahan, Douglas ;

Weinberg, Robert A. .

CELL, 2011, 144 (05) :646-674

[9] Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer [J].

Hann, Christine L. ;

Daniel, Vincent C. ;

Sugar, Elizabeth A. ;

Dobromilskaya, Irina ;

Murphy, Sara C. ;

Cope, Leslie ;

Lin, Xue ;

Hierman, Jared S. ;

Wilburn, Daniel L. ;

Watkins, D. Neil ;

Rudin, Charles M. .

CANCER RESEARCH, 2008, 68 (07) :2321-2328

[10] Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein [J].

Li, YW ;

Upadhyay, S ;

Bhuiyan, M ;

Sarkar, FH .

ONCOGENE, 1999, 18 (20) :3166-3172

← 1 2 →