Abstract：
:Anti-apoptotic BCL-2 family proteins block cell death by trapping the critical α-helical BH3 domains of pro-apoptotic members in a surface groove. Cancer cells hijack this survival mechanism by overexpressing a spectrum of anti-apoptotic members, mounting formidable apoptotic blockades that resist chemotherapeutic treatment. Drugging the BH3-binding pockets of anti-apoptotic proteins has become a highest-priority goal, fueled by the clinical success of ABT-199, a selective BCL-2 inhibitor, in reactivating apoptosis in BCL-2-dependent cancers. BFL-1 is a BCL-2 homolog implicated in melanoma, lymphoma, and other cancers, and remains undrugged. A natural juxtaposition of two unique cysteines at the binding interface of the NOXA BH3 helix and BFL-1 pocket informed the development of stapled BH3 peptides bearing acrylamide warheads to irreversibly inhibit BFL-1 by covalent targeting. Given the frequent proximity of native cysteines to regulatory binding surfaces, covalent stapled peptide inhibitors provide a new therapeutic strategy for targeting pathologic protein interactions.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Huhn AJ,Guerra RM,Harvey EP,Bird GH,Walensky LDdoi
10.1016/j.chembiol.2016.07.022subject
Has Abstractpub_date
2016-09-22 00:00:00pages
1123-1134issue
9eissn
2451-9456issn
2451-9448pii
S2451-9456(16)30289-6journal_volume
23pub_type
杂志文章abstract：:The unique photophysical properties of lanthanides, such as europium, terbium, and ytterbium, make them versatile molecular probes of biological systems. In particular, their long-lived photoluminescence, narrow bandwidth emissions, and large Stokes shifts enable experiments that are infeasible with organic fluorophor...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2020.07.009
更新日期：2020-08-20 00:00:00
abstract：:The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2021.01.005
更新日期：2021-01-22 00:00:00
abstract：:In this issue of Cell Chemical Biology, Ortega et al. (2016) determine the structure of another lantibiotic dehydratase with a tRNA(Glu)-dependent mechanism of modification. Moreover, they identify a common recognition motif involved in leader peptide binding in a number of different peptide-modification enzymes. Thes...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.03.001
更新日期：2016-03-17 00:00:00
abstract：:Energy coupling factor (ECF) transporters are responsible for the uptake of essential scarce nutrients in prokaryotes. This ATP-binding cassette transporter family comprises two subgroups that share a common architecture forming a tripartite membrane protein complex consisting of a translocation component and ATP hydr...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.06.008
更新日期：2016-07-21 00:00:00
abstract：:While the wound healing property of the macrolide FK506 is well known, the underlying mechanism has been elusive. In this issue of Cell Chemical Biology, Peiffer et al. (2019) utilize FKBP12 ligand to demonstrate that wound healing effects of FK506 occur via activation of the BMP (bone morphogenic protein) signaling p...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.05.001
更新日期：2019-05-16 00:00:00
abstract：:G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel singl...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.08.013
更新日期：2016-10-20 00:00:00
abstract：:Disorders of bone healing and remodeling are indications with an unmet need for effective pharmacological modulators. We used a high-throughput screen to identify activators of the bone marker alkaline phosphatase (ALP), and discovered 6,8-dimethyl-3-(4-phenyl-1H-imidazol-5-yl)quinolin-2(1H)-one (DIPQUO). DIPQUO marke...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.03.009
更新日期：2019-07-18 00:00:00
abstract：:Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferrop...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.09.014
更新日期：2019-12-19 00:00:00
abstract：:The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.01.011
更新日期：2018-04-19 00:00:00
abstract：:This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2017.05.023
更新日期：2017-07-20 00:00:00
abstract：:Epidermal growth factor receptor (EGFR) is a target of signal-derived H2O2, and oxidation of active-site cysteine 797 to sulfenic acid enhances kinase activity. Although a major class of covalent drugs targets C797, nothing is known about its catalytic importance or how S-sulfenylation leads to activation. Here, we re...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.05.017
更新日期：2016-07-21 00:00:00
abstract：:Optically controlled chemical reagents, termed "photopharmaceuticals," are powerful tools for precise spatiotemporal control of proteins particularly when genetic methods, such as knockouts or optogenetics are not viable options. However, current photopharmaceutical scaffolds, such as azobenzenes are intolerant of GFP...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.11.007
更新日期：2020-11-27 00:00:00
abstract：:Dengue virus infects more than 300 million people annually, yet there is no widely protective vaccine or drugs against the virus. Efforts to develop antivirals against classical targets such as the viral protease and polymerase have not yielded drugs that have advanced to the clinic. Here, we show that the allosteric ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.03.010
更新日期：2016-04-21 00:00:00
abstract：:The engineered ascorbate peroxidase (APEX) is a powerful tool for the proximity-dependent labeling of proteins and RNAs in live cells. Although widely use in mammalian cells, APEX applications in microorganisms have been hampered by the poor labeling efficiency of its biotin-phenol (BP) substrate. In this study, we so...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.05.006
更新日期：2020-07-16 00:00:00
abstract：:The spliceosome mediates precursor mRNA splicing in eukaryotes, including the model organism Saccharomyces cerevisiae (yeast). Despite decades of study, no chemical inhibitors of yeast splicing in vivo are available. We have developed a system to efficiently inhibit splicing and block proliferation in living yeast cel...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.11.008
更新日期：2019-03-21 00:00:00
abstract：:Ubiquinone (UQ) is a conserved polyprenylated lipid essential to cellular respiration. Two papers, one in this issue of Cell Chemical Biology (Hajj Chehade et al., 2019) and another in Molecular Cell (Lohman et al., 2019), identify lipid-binding proteins that play crucial roles in chaperoning UQ-intermediates. ...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.04.005
更新日期：2019-04-18 00:00:00
abstract：:Electron microscopy (EM) remains the primary method for imaging cellular and tissue ultrastructure, although simultaneous localization of multiple specific molecules continues to be a challenge for EM. We present a method for obtaining multicolor EM views of multiple subcellular components. The method uses sequential,...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.10.006
更新日期：2016-11-17 00:00:00
abstract：:Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphopr...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.01.007
更新日期：2020-03-19 00:00:00
abstract：:Eicosanoids and related oxylipins are critical, small bioactive mediators of human physiology and inflammation. While ∼1,100 distinct species have been predicted to exist, to date, less than 150 of these molecules have been measured in humans, limiting our understanding of their role in human biology. Using a directed...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.11.015
更新日期：2019-03-21 00:00:00
abstract：:Acyl-coenzyme A (CoA)/protein interactions are essential for life. Despite this importance, their global scope and selectivity remains undefined. Here, we describe CATNIP (CoA/AcetylTraNsferase Interaction Profiling), a chemoproteomic platform for the high-throughput analysis of acyl-CoA/protein interactions in endoge...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.11.011
更新日期：2020-03-19 00:00:00
abstract：:Despite the urgent need for assays to visualize insulin secretion there is to date no reliable method available for measuring insulin release from single cells. To address this need, we developed a genetically encoded reporter termed RINS1 based on proinsulin superfolder GFP (sfGFP) and mCherry fusions for monitoring ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.03.001
更新日期：2017-04-20 00:00:00
abstract：:Using light to control cellular processes is one of the attractive areas of research. Here, availability of different, light-responsive caged compounds has played a critical role. In this issue of Cell Chemical Biology, Hövelmann et al. (2016) give us an example of how to design and use caged lipids to guide chemotaxi...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.05.003
更新日期：2016-05-19 00:00:00
abstract：:ATP is an important energy metabolite and allosteric signal in health and disease. ATP-interacting proteins, such as P2 receptors, control inflammation, cell death, migration, and wound healing. However, identification of allosteric ATP sites remains challenging, and our current inventory of ATP-controlled pathways is...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.05.010
更新日期：2020-08-20 00:00:00
abstract：:Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.12.006
更新日期：2021-01-05 00:00:00
abstract：:In this issue of Cell Chemical Biology, Olson et al. (2019) develop the first selective CDK7 irreversible inhibitor. Elegant cell-based studies using a CDK7 mutant that is not covalently engaged by the probe helped decipher the effects of inhibiting the kinase on the cell cycle and gene transcription. ...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.05.012
更新日期：2019-06-20 00:00:00
abstract：:Recent advances in induced pluripotent stem cell technologies and phenotypic screening shape the future of bioactive small-molecule discovery. In this review we analyze the impact of small-molecule phenotypic screens on drug discovery as well as on the investigation of human development and disease biology. We further...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2019.05.007
更新日期：2019-08-15 00:00:00
abstract：:Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.07.004
更新日期：2018-10-18 00:00:00
abstract：:Infections with Salmonella enterica pose a challenge for antibiotic treatment. In this issue of Cell Chemical Biology, Tsai et al. use a chemical genomics approach to identify dephostatin as an inhibitor of intracellular Salmonella virulence in vitro and in vivo by targeting the two-component systems SsrA-SsrB and Pmr...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.06.017
更新日期：2020-07-16 00:00:00
abstract：:Depalmitoylases play a crucial role in regulating dynamic protein palmitoylation. In this issue of Cell Chemical Biology, Amara et al. (2019) present fluorogenic peptide probes to analyze the activity and substrate specificity of depalmitoylases and uncover that the amino acid residues distal to the palmitoylation sit...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2018.12.008
更新日期：2019-01-17 00:00:00
abstract：:In the nematode Caenorhabditis elegans, inactivating mutations in the insulin/IGF-1 receptor, DAF-2, result in a 2-fold increase in lifespan mediated by DAF-16, a FOXO-family transcription factor. Downstream protein activities that directly regulate longevity during impaired insulin/IGF-1 signaling (IIS) are poorly ch...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.06.015
更新日期：2016-08-18 00:00:00
