scholarly journals Selective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs

2020 ◽  
Vol 13 (4) ◽  
pp. 74
Author(s):  
Minoru Ishikawa ◽  
Shusuke Tomoshige ◽  
Yosuke Demizu ◽  
Mikihiko Naito
Keyword(s):  
Small Molecules ◽  
Target Proteins ◽  
Therapeutic Modalities ◽  
Selective Degradation ◽  
Apoptosis Protein ◽  
Ubiquitin Ligase E3 ◽  
Dependent Protein ◽  
Specific Proteins ◽  
Degradation Activity ◽  
Chimeric Molecules

New therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One possible approach is the induction of protein degradation by chimeric drugs composed of a ubiquitin ligase (E3) ligand coupled to a ligand for the target protein. This article reviews chimeric drugs that decrease the level of specific proteins such as proteolysis targeting chimeric molecules (PROTACs) and specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which target proteins for proteasome-mediated degradation. We cover strategies for increasing the degradation activity induced by small molecules, and their scope for application to undruggable proteins.

scholarly journals Targeted Protein Degradation by Chimeric Compounds using Hydrophobic E3 Ligands and Adamantane Moiety

2020 ◽  
Vol 13 (3) ◽  
pp. 34
Author(s):  
Takuji Shoda ◽  
Nobumichi Ohoka ◽  
Genichiro Tsuji ◽  
Takuma Fujisato ◽  
Hideshi Inoue ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Inhibitors Of Apoptosis ◽  
Target Proteins ◽  
Aryl Hydrocarbon ◽  
Apoptosis Protein ◽  
Dependent Protein ◽  
New Compounds ◽  
Chimeric Molecules ◽  
Tagging System ◽  
In Cells

Targeted protein degradation using small chimeric molecules, such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs), is a promising technology in drug discovery. We recently developed a novel class of chimeric compounds that recruit the aryl hydrocarbon receptor (AhR) E3 ligase complex and induce the AhR-dependent degradation of target proteins. However, these chimeras contain a hydrophobic AhR E3 ligand, and thus, degrade target proteins even in cells that do not express AhR. In this study, we synthesized new compounds in which the AhR ligands were replaced with a hydrophobic adamantane moiety to investigate the mechanisms of AhR-independent degradation. Our results showed that the compounds, 2, 3, and 16 induced significant degradation of some target proteins in cells that do not express AhR, similar to the chimeras containing AhR ligands. However, in cells expressing AhR, 2, 3, and 16 did not induce the degradation of other target proteins, in contrast with their response to chimeras containing AhR ligands. Overall, it was suggested that target proteins susceptible to the hydrophobic tagging system are degraded by chimeras containing hydrophobic AhR ligands even without AhR.

scholarly journals Development of an N-Terminal BRD4 Bromodomain-Targeted Degrader

2021 ◽  
Author(s):  
Anand Divakaran ◽  
Huda Zahid ◽  
Wenwei Lin ◽  
Taosheng Chen ◽  
Dan Harki ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Small Molecules ◽  
Ubiquitin Ligase ◽  
Ternary Complex ◽  
Selective Inhibitor ◽  
Selective Degradation ◽  
Ternary Complex Formation ◽  
Native Proteins ◽  
Bet Inhibitors ◽  
Ubiquitin Ligase E3

Targeted protein degradation is a powerful induced-proximity tool to control cellular concentrations of native proteins using small molecules. However, the design of selectivity in protein degradation remains challenging. In the case of Bromodomain and Extra-Terminal (BET) family proteins, BRD4 has emerged as the primary therapeutic target over other family members BRD2, 3 and T, but strategies to selectively degrade BRD4 rely on the use of pan-BET inhibitors optimized for BRD4:E3 protein-ubiquitin ligase (E3) ternary complex formation. Here, we report a potent and selective inhibitor for the first bromodomain of BRD4, iBRD4-BD1 (IC50 = 12 nM, 23-6200-fold intra-BET selectivity). We further use this novel inhibitor to develop dBRD4-BD1 that induces selective degradation of BRD4 at a DC50 of 280 nM. The design of BRD4 selectivity up-front enables the study of BRD4 biology in the absence of wider BET-inhibition, simplifies design of future BRD4-selective degraders as new E3 recruiting ligands are discovered, and provides a tool to design additional heterobifunctional BRD4-selective probes.

scholarly journals Therapeutic Advances in Oncology

2021 ◽  
Vol 22 (4) ◽  
pp. 2008
Author(s):  
Jinsha Liu ◽  
Priyanka Pandya ◽  
Sepideh Afshar
Keyword(s):  
Small Molecules ◽  
New Technologies ◽  
Treatment Options ◽  
Current Treatment ◽  
Bispecific Antibodies ◽  
Gene Therapies ◽  
Therapeutic Modalities ◽  
The Past ◽  
Drug Conjugates ◽  
Novel Targets

Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.

scholarly journals Emerging Therapeutic Modalities against COVID-19

2020 ◽  
Vol 13 (8) ◽  
pp. 188 ◽  
Author(s):  
Shipra Malik ◽  
Anisha Gupta ◽  
Xiaobo Zhong ◽  
Theodore P. Rasmussen ◽  
Jose E. Manautou ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Therapeutic Interventions ◽  
Pharmaceutical Companies ◽  
The Novel ◽  
Comprehensive Overview ◽  
Therapeutic Modalities ◽  
Academic Researchers ◽  
Approved Drugs ◽  
Fda Approved Drugs

The novel SARS-CoV-2 virus has quickly spread worldwide, bringing the whole world as well as the economy to a standstill. As the world is struggling to minimize the transmission of this devastating disease, several strategies are being actively deployed to develop therapeutic interventions. Pharmaceutical companies and academic researchers are relentlessly working to investigate experimental, repurposed or FDA-approved drugs on a compassionate basis and novel biologics for SARS-CoV-2 prophylaxis and treatment. Presently, a tremendous surge of COVID-19 clinical trials are advancing through different stages. Among currently registered clinical efforts, ~86% are centered on testing small molecules or antibodies either alone or in combination with immunomodulators. The rest ~14% of clinical efforts are aimed at evaluating vaccines and convalescent plasma-based therapies to mitigate the disease's symptoms. This review provides a comprehensive overview of current therapeutic modalities being evaluated against SARS-CoV-2 virus in clinical trials.

scholarly journals Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone

2020 ◽  
Vol 27 (3) ◽  
pp. 292-305.e6 ◽  
Author(s):  
Jay K. Singh ◽  
Darren M. Hutt ◽  
Bradley Tait ◽  
Naihsuan C. Guy ◽  
Jeffrey C. Sivils ◽  
...  
Keyword(s):  
Protein Folding ◽  
Small Molecules ◽  
Dependent Protein

The cis-acting signals that target proteins to exosomes and microvesicles

2013 ◽  
Vol 41 (1) ◽  
pp. 277-282 ◽  
Author(s):  
Jr-Ming Yang ◽  
Stephen J. Gould
Keyword(s):  
Quality Control ◽  
Nucleic Acids ◽  
Cell Polarity ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Target Proteins ◽  
Cis Acting ◽  
Vesicle Traffic ◽  
Specific Proteins ◽  
Targeting Signals

Proteins bud from cells in small single-membraned vesicles (~50–250 nm) that have the same topology as the cell. Known variously as exosomes and microvesicles (EMVs), these extracellular organelles are enriched for specific proteins, lipids, carbohydrates and nucleic acids. EMV biogenesis plays critical roles in protein quality control and cell polarity, and, once released, EMVs can transmit signals and molecules to neighbouring cells via a non-viral pathway of intercellular vesicle traffic. In the present paper, we discuss the cis-acting targeting signals that target proteins to EMVs and mediate protein budding from the cell.

scholarly journals Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation

2021 ◽  
Vol 9 ◽  
Author(s):  
Ming He ◽  
Wenxing Lv ◽  
Yu Rao
Keyword(s):  
Rna Interference ◽  
Protein Degradation ◽  
Small Molecules ◽  
Small Molecule ◽  
Gene Editing ◽  
Small Molecule Inhibitors ◽  
Tumor Resistance ◽  
Target Proteins ◽  
Enzymatic Function ◽  
New Type

Proteolysis targeting chimeras (PROTAC) represents a new type of small molecule induced protein degradation technology that has emerged in recent years. PROTAC uses bifunctional small molecules to induce ubiquitination of target proteins and utilizes intracellular proteasomes for chemical knockdown. It complements the gene editing and RNA interference for protein knockdown. Compared with small molecule inhibitors, PROTAC has shown great advantages in overcoming tumor resistance, affecting the non-enzymatic function of target proteins, degrading undruggable targets, and providing new rapid and reversible chemical knockout tools. At the same time, its challenges and problems also need to be resolved as a fast-developing newchemical biology technology.

scholarly journals Mechanism-based sirtuin enzyme activation

2015 ◽  
Author(s):  
Xiangying Guan ◽  
Alok Upadhyay ◽  
Sudipto Munshi ◽  
Raj Chakrabarti
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
False Positives ◽  
Enzyme Activation ◽  
Label Free ◽  
Multiple Substrates ◽  
Dependent Protein ◽  
Biophysical Techniques ◽  
Catalyzed Reactions ◽  
Small Molecule Modulators

AbstractSirtuin enzymes are NAD+-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals. There is intense interest in the activation of the seven mammalian sirtuins (SIRT1-7) in order to extend mammalian healthspan and lifespan. However, there is currently no understanding of how to design sirtuin-activating compounds beyond allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates. Moreover, across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. None of these modes of activation are based on the unique catalytic reaction mechanisms of the target enzymes. Here, we report a general mode of sirtuin activation that is distinct from the known modes of enzyme activation. Based on the conserved mechanism of sirtuin-catalyzed deacylation reactions, we establish biophysical properties of small molecule modulators that can in principle result in enzyme activation for diverse sirtuins and substrates. Building upon this framework, we propose strategies for the identification, characterization and evolution of hits for mechanism-based enzyme activating compounds. We characterize several small molecules reported in the literature to activate sirtuins besides SIRT1, using a variety of biochemical and biophysical techniques including label-free and labeled kinetic and thermodynamic assays with multiple substrates and protocols for the identification of false positives. We provide evidence indicating that several of these small molecules reported in the published literature are false positives, and identify others as hit compounds for the design of compounds that can activate sirtuins through the proposed mechanism-based mode of action.

scholarly journals Deubiquitinase-Targeting Chimeras for Targeted Protein Stabilization

2021 ◽  
Author(s):  
Nathaniel J. Henning ◽  
Lydia Boike ◽  
Jessica N. Spradlin ◽  
Carl C. Ward ◽  
Bridget Belcher ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein Stabilization ◽  
Therapeutic Modality ◽  
Dependent Manner ◽  
Bronchial Epithelial ◽  
Therapeutic Modalities ◽  
Ligand Discovery ◽  
Δf508 Cftr ◽  
Specific Proteins ◽  
Cftr Protein

AbstractTargeted protein degradation is a powerful therapeutic modality that uses heterobifunctional small-molecules to induce proximity between E3 ubiquitin ligases and target proteins to ubiquitinate and degrade specific proteins of interest. However, many proteins are ubiquitinated and degraded to drive disease pathology; in these cases targeted protein stabilization (TPS), rather than degradation, of the actively degraded target using a small-molecule would be therapeutically beneficial. Here, we present the Deubiquitinase-Targeting Chimera (DUBTAC) platform for TPS of specific proteins. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48 ubiquitin-specific deubiquitinase OTUB1. We then developed a heterobifunctional DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-CFTR. We demonstrated proof-of-concept of TPS by showing that this DUBTAC robustly stabilized ΔF508-CFTR in human cystic fibrosis bronchial epithelial cells in an OTUB1-dependent manner. Our study underscores the utility of chemoproteomics-enabled covalent ligand discovery approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.Editorial summaryWe have developed the Deubiquitinase Targeting Chimera (DUBTAC) platform for targeted protein stabilization. We have discovered a covalent recruiter against the deubiquitinase OTUB1 that we have linked to the mutant ΔF508-CFTR targeting cystic fibrosis drug Lumacaftor to stabilize mutant CFTR protein in cells.

scholarly journals A Proteomic Platform to Identify Off-Target Proteins Associated with Therapeutic Modalities that Induce Protein Degradation or Gene Silencing

2021 ◽  
Author(s):  
Xin Liu ◽  
Ye Zhang ◽  
Lucas D. Ward ◽  
Qinghong Yan ◽  
Tanggis Bohnuud ◽  
...  
Keyword(s):  
Cell Lines ◽  
Selection Process ◽  
Extracellular Proteins ◽  
Label Free ◽  
Target Proteins ◽  
Therapeutic Modalities ◽  
Endogenous Proteins ◽  
Or Gene ◽  
Target Binding

Abstract Novel modalities such as Proteolysis Targeting Chimera (PROTAC) and RNA interference (RNAi) have the ability to inadvertently alter the abundance of endogenous proteins. Currently available in vitro secondary pharmacology assays, which evaluate off-target binding or activity of small molecules, do not fully assess the off-target effects of PROTAC and are not applicable to RNAi. To address this gap, we developed a proteomics-based platform to comprehensively evaluate abundance of off-target proteins. The first part of the study involves selecting a panel of off-target proteins and a platform of cell lines using evidence from genetics and pharmacology. This process yielded 2,813 proteins, forming the basis of a panel that we refer to as the “selected off-target proteome” (SOTP). An iterative algorithm was then used to identify appropriate cell lines. Four human cell lines out of 932 were selected that, collectively, expressed ~ 80% of the SOTP based on transcriptome data. Second, we used mass spectrometry to quantify the intracellular and extracellular proteins of interest in the 4 selected cell lines. Among over 10,000 quantifiable proteins identified, 1,828 were part of the predefined SOTP. The SOTP was designed to be easily modified or expanded, owing rationale selection process developed and the label free LC-MS/MS approach chosen. This versatility inherent to our platform is essential to design fit-for-purpose studies that can address the dynamic questions faced in investigative toxicology.

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