Abstract：
:Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Aleem S,Georghiou G,Kleiner RE,Guja K,Craddock BP,Lyczek A,Chan AI,Garcia-Diaz M,Miller WT,Liu DR,Seeliger MAdoi
10.1016/j.chembiol.2016.07.017subject
Has Abstractpub_date
2016-09-22 00:00:00pages
1103-1112issue
9eissn
2451-9456issn
2451-9448pii
S2451-9456(16)30254-9journal_volume
23pub_type
杂志文章abstract：:New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional kinase degraders are compared with ATP site ligands that were serendipitously found to cause kinase downregulation. These approaches could be particul...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2017.10.011
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abstract：:Activation of innate immune signaling in the tumor microenvironment is central to a successful anti-tumor immune response, and it is in large part mediated by cytosolic double-stranded DNA sensing. Here, Carozza et al. (2020b) report potent and selective inhibitors of ENPP1, a negative regulator of innate immune signa...
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abstract：:Sirtuins are a large enzyme family involved in installing and removing post-translational modifications involving lysine side chains. These enzymes have been of intense research interest and we now understand many details of their mechanism, although later steps of the deacetylase activity have remained a mystery. In ...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2017.03.004
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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
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abstract：:Pharmacophore-focused chemical libraries are continuously being created in drug discovery programs, yet screening assays to maximize the usage of such libraries are not fully explored. Here, we report a chemical proteomics approach to reutilizing a focused chemical library of 1,800 indole-containing molecules for disc...
journal_title：Cell chemical biology
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更新日期：2020-06-18 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
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doi：10.1016/j.chembiol.2020.12.006
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abstract：:Chemical strategies to block quorum sensing (QS) could provide a route to attenuate virulence in bacterial pathogens. Considerable research has focused on this approach in Pseudomonas aeruginosa, which uses the LuxR-type receptor LasR to regulate much of its QS network. Non-native ligands that antagonize LasR have bee...
journal_title：Cell chemical biology
pub_type： 杂志文章
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abstract：:Antibiotic resistance is a rapidly evolving health concern that requires a sustained effort to understand mechanisms of resistance and to develop new agents that overcome those mechanisms. The dihydrofolate reductase (DHFR) inhibitor, trimethoprim (TMP), remains one of the most important orally administered antibiotic...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.11.007
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abstract：:The discovery of novel small molecules that induce stem cell reprogramming and give efficient access to pluripotent stem cells is of major importance for potential therapeutic applications and may reveal novel insights into the factors controlling pluripotency. Chemical reprogramming of mouse epiblast stem cells (EpiS...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.02.015
更新日期：2016-04-21 00:00:00
abstract：:Phenotypic drug discovery offers some advantages over target-based methods, mainly because it allows drug leads to be tested in systems that more closely model distinct disease states. However, a potential disadvantage is the difficulty of linking the observed phenotype to a specific cellular target. To address this p...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.08.011
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abstract：:Identification and validation of the targets of bioactive small molecules identified in cell-based screening is challenging and often meets with failure, calling for the development of new methodology. We demonstrate that a combination of chemical proteomics with in silico target prediction employing the SPiDER method...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.05.016
更新日期：2018-09-20 00:00:00
abstract：:Because small-molecule activators of adenylyl cyclases (AC) affect ACs cell-wide, it is challenging to explore the signaling consequences of AC activity emanating from specific intracellular compartments. We explored this issue using a series of engineered, optogenetic, spatially restricted, photoactivable adenylyl cy...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.07.004
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abstract：:USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.09.004
更新日期：2017-12-21 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：:The accumulation of α-synuclein amyloid fibrils in the brain is linked to Parkinson's disease and other synucleinopathies. The intermediate species in the early aggregation phase of α-synuclein are involved in the emergence of amyloid toxicity and considered to be the most neurotoxic. The N-terminal region flanking th...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.12.010
更新日期：2021-01-06 00:00:00
abstract：:In this issue of Cell Chemical Biology, Sakin et al. (2017) investigate the nanoscale behavior of the HIV-1 envelope (Env) glycoprotein complex by using genetic code expansion, bioorthogonal amino acids, synthetic dyes, and click chemistry. This minimally invasive approach allows the measurement of native Env cellular...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.05.006
更新日期：2017-05-18 00:00:00
abstract：:In this issue of Cell Chemical Biology, Radlinski et al. (2019) identify Pseudomonas-derived rhamnolipids that potentiate aminoglycoside antibiotics in the eradication of antibiotic-tolerant bacterial phenotypes. Microbial physiological and mechanistic studies indicate that rhamnolipids permeabilize S. aureus membrane...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.09.015
更新日期：2019-10-17 00:00:00
abstract：:4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-HIV type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4'-moiety and potently inhibit the replication of a wide spectrum of HIV-1 st...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.07.014
更新日期：2018-10-18 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
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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
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abstract：:Mycobacterium tuberculosis synthesizes a wide variety of complex lipids that can serve as antigens in immune recognition of the bacterium. In this issue of Cell Chemical Biology, Gilleron et al. (2016) identify key enzymes essential for lipid antigen processing, which is required for CD1b-restricted T cell activation....
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2016.09.005
更新日期：2016-09-22 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
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更新日期：2019-04-18 00:00:00
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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：: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：:Alternative polyadenylation (APA) plays a critical role in regulating gene expression. However, the balance between genome-encoded APA processing and autoregulation by APA modulating RNA binding protein (RBP) factors is not well understood. We discovered two potent small-molecule modulators of APA (T4 and T5) that pro...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.09.006
更新日期：2018-12-20 00:00:00
abstract：:Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform select...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.10.008
更新日期：2016-11-17 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：:Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.09.007
更新日期：2017-12-21 00:00:00
abstract：:A picture may speak a thousand words, but if those words fail to form a coherent sentence there is little to be learned. As cutting-edge imaging technology now provides us the tools to decipher the multitude of roles played by metals and metalloids in molecular, cellular, and developmental biology, as well as health a...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2017.10.006
更新日期：2018-01-18 00:00:00
abstract：:Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of informati...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.02.003
更新日期：2018-05-17 00:00:00
