Abstract
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.
Highlights
Cancer develops through a multistep complex process that involves a series of genetic and epigenetic alterations which in turn, lead to malignant phenotypes [1,2,3,4]
This study demonstrated that the 1,4-thienodiazepine-2,5-dione scaffold is bioisosteric to the well known benzodiazepinediones and perhaps by correlation, may be a bioisosteric privileged structure
Enumeration of the scaffold followed by plotting molecular weight (MW) vs. TPSA, compared to available benzodiazepine compounds through eMolecules [70], suggests that there is a large potential diversity which can be accessed based on the developed chemistry
Summary
Cancer develops through a multistep complex process that involves a series of genetic and epigenetic alterations which in turn, lead to malignant phenotypes [1,2,3,4]. Examples of effective targeted therapies that have entered clinical use are: proteasome inhibitor bortezomib which has improved the median survival of multiple myeloma patients [10,11], several tyrosine kinase inhibitors effective against renal and lung cancer [12], mTOR inhibitors [13], and lately, DNA methylation and chromatin modifying epigenetic drugs [14,15] All this new therapeutic armamentarium has had, little effect on the ultimate clinical outcome of most cancers [16]. Notable attempts to compare NP collections with other synthetic collections have been described [38,39], providing empirical evidence of higher polarity, decreased hydrophobicity, higher molecular weights, increased stereochemical features and higher sp content [40], unique molecular architectures and fewer aromatic rings [31] These strategies are a clever way to address the shortcomings of using unguided combinatorial chemistry techniques [41,42] in the absence of other traditional structure-guided approaches. The inhibitor (colored in yellow) is able to mimic hot spot residues (colored in purple) implicated in the p53-Mdm interface [47]
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