Targeting Oncogenic Protein-Protein Interactions by Diversity Oriented Synthesis and Combinatorial Chemistry Approaches

被引:14
作者
Tzakos, Andreas G. [1 ,2 ]
Fokas, Demosthenes [3 ]
Johannes, Charlie [4 ]
Moussis, Vassilios [2 ]
Hatzimichael, Eleftheria [5 ]
Briasoulis, Evangelos [1 ,5 ,6 ]
机构
[1] Univ Ioannina, Human Canc Biobank Ctr, GR-45110 Ioannina, Greece
[2] Univ Ioannina, Dept Chem, GR-45110 Ioannina, Greece
[3] Univ Ioannina, Dept Mat Sci & Engn, GR-45110 Ioannina, Greece
[4] Inst Chem & Engn Sci, Singapore 138667, Singapore
[5] Univ Hosp Ioannina, Dept Clin Hematol, GR-45110 Ioannina, Greece
[6] Univ Ioannina, Sch Med, Oncol Sect, GR-45110 Ioannina, Greece
关键词
diversity-oriented synthesis; combinatorial chemistry; protein-protein interactions; cancer; SMALL-MOLECULE ANTAGONISTS; BCL-2 FAMILY PROTEINS; C-MYC; NATURAL-PRODUCTS; P53; PATHWAY; DRUG DISCOVERY; CANCER; INHIBITORS; IDENTIFICATION; APOPTOSIS;
D O I
10.3390/molecules16064408
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
We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions.
引用
收藏
页码:4408 / 4427
页数:20
相关论文
共 104 条
[1]   The Bcl-2 inhibitor ABT-263 enhances the response of multiple chemotherapeutic regimens in hematologic tumors in vivo [J].
Ackler, Scott ;
Mitten, Michael J. ;
Foster, Kelly ;
Oleksijew, Anatol ;
Refici, Marion ;
Tahir, Stephen K. ;
Xiao, Yu ;
Tse, Christin ;
Frost, David J. ;
Fesik, Stephen W. ;
Rosenberg, Saul H. ;
Elmore, Steven W. ;
Shoemaker, Alexander R. .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2010, 66 (05) :869-880
[2]   The Bcl-2 protein family: Arbiters of cell survival [J].
Adams, JM ;
Cory, S .
SCIENCE, 1998, 281 (5381) :1322-1326
[3]   Genetic variegation of clonal architecture and propagating cells in leukaemia [J].
Anderson, Kristina ;
Lutz, Christoph ;
van Delft, Frederik W. ;
Bateman, Caroline M. ;
Guo, Yanping ;
Colman, Susan M. ;
Kempski, Helena ;
Moorman, Anthony V. ;
Titley, Ian ;
Swansbury, John ;
Kearney, Lyndal ;
Enver, Tariq ;
Greaves, Mel .
NATURE, 2011, 469 (7330) :356-+
[4]  
[Anonymous], 2010, United States Pat, Patent No. 7851637
[5]  
[Anonymous], CA CANC J CLIN, DOI DOI 10.3322/CAAC.20107
[6]  
[Anonymous], ANCHOR
[7]   Proteins, drug targets and the mechanisms they control: the simple truth about complex networks [J].
Araujo, Robyn P. ;
Liotta, Lance A. ;
Petricoin, Emanuel F. .
NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (11) :871-880
[8]   Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream [J].
Arkin, MR ;
Wells, JA .
NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) :301-317
[9]   Binding of small molecules to an adaptive protein-protein interface [J].
Arkin, MR ;
Randal, M ;
DeLano, WL ;
Hyde, J ;
Luong, TN ;
Oslob, JD ;
Raphael, DR ;
Taylor, L ;
Wang, J ;
McDowell, RS ;
Wells, JA ;
Braisted, AC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (04) :1603-1608
[10]   Molecular targets for breast cancer therapy and prevention [J].
Bange, J ;
Zwick, E ;
Ullrich, A .
NATURE MEDICINE, 2001, 7 (05) :548-552