Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer.
01 Jan 2019-Current Topics in Medicinal Chemistry (Bentham Science Publishers Ltd.)-Vol. 19, Iss: 6, pp 457-466
TL;DR: Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases.
Abstract: Background Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects. Objective In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer. Methods Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs. Results The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges. Conclusion Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.
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TL;DR: Drug repositioning introduces an affordable and efficient strategy to discover novel drug action, especially when integrated with recent systems biology driven stratagem, in combination with conventional anticancer agents to combat drug resistance in the near future.
20 citations
TL;DR: A novel attempt in terms of blending scaffold hopping and hierarchical virtual screening in order to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2).
Abstract: BACKGROUND Though virtual screening methods have proven to be potent in various instances, the technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now, in all the previous attempts these two approaches were applied separately. OBJECTIVE In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2). METHODS We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching. RESULTS We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds. CONCLUSION Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.
5 citations
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458 citations
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375 citations
TL;DR: In in vitro studies, primary cells from patients with various B-cell malignancies are exquisitely sensitive to ABT-737, exhibiting novel morphological features of apoptosis including marked outer mitochondrial membrane rupture.
Abstract: Despite tremendous advances over the last 15 years in understanding fundamental mechanisms of apoptosis, this has failed to translate into improved cancer therapy for patients. However, there may now be light at the end of this long tunnel. Antiapoptotic Bcl-2 family members may be divided into two subclasses, one comprising Bcl-2, Bcl-XL and Bcl-w and the other Mcl-1 and Bcl2A1. Neutralization of both subclasses is required for apoptosis induction. Solution of the structure of antiapoptotic Bcl-2 family proteins has led to the design of novel small molecule inhibitors. Although many such molecules have been synthesized, rigorous verification of their specificity has often been lacking. Further studies have revealed that many putative Bcl-2 inhibitors are not specific and have other cellular targets, resulting in non-mechanism based toxicity. Two notable exceptions are ABT-737 and a related orally active derivative, ABT-263, which bind with high affinity to Bcl-2, Bcl-XL and Bcl-w and may prove to be useful tools for mechanistic studies. ABT-263 is in early clinical trials in lymphoid malignancies, small-cell lung cancer and chronic lymphocytic leukemia, and some patients have shown promising results. In in vitro studies, primary cells from patients with various B-cell malignancies are exquisitely sensitive to ABT-737, exhibiting novel morphological features of apoptosis including marked outer mitochondrial membrane rupture.
362 citations
TL;DR: It is concluded that peptide stapling and fragment-based drug discovery show promise to traverse the critical surface features of proteins that drive human cancer.
Abstract: The genomic and proteomic revolutions have provided us with an ever-increasing number of mechanistic insights into cancer pathogenesis. Mutated genes and pathologic protein products have emerged as the basis for modern anticancer drug development. With the increasing realization of the importance of disrupting oncogenic protein-protein interaction, new challenges have emerged for classical small molecule and protein-based drug modalities, i.e., the critical need to target flat and extended protein surfaces. Here, we highlight two distinct technologies that are being used to bridge the pharmacologic gap between small molecules and protein therapeutics. With the BCL-2 family of survival proteins as their substrate for intracellular targeting, we conclude that peptide stapling and fragment-based drug discovery show promise to traverse the critical surface features of proteins that drive human cancer.
354 citations
01 Aug 2010
TL;DR: X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity, and generated an MCL-1-specific agent that defines the structural and functional features of targeted M CL-1 inhibition.
Abstract: The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition.
316 citations