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 problem, we developed DePick, a computational target de-convolution tool to determine targets specifically linked to small-molecule phenotypic screens. We applied DePick to eight publicly available screens and predicted 59 drug target-phenotype associations. In addition to literature-based evidence for our predictions, we provide experimental support for seven predicted associations. Interestingly, our analysis led to the discovery of a previously unrecognized connection between the Wnt signaling pathway and an aromatase, CYP19A1. These results demonstrate that the DePick approach can not only accelerate target de-convolution but also aid in discovery of new functionally relevant biological relationships.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Liu X,Baarsma HA,Thiam CH,Montrone C,Brauner B,Fobo G,Heier JS,Duscha S,Königshoff M,Angeli V,Ruepp A,Campillos Mdoi
10.1016/j.chembiol.2016.08.011subject
Has Abstractpub_date
2016-10-20 00:00:00pages
1302-1313issue
10eissn
2451-9456issn
2451-9448pii
S2451-9456(16)30294-Xjournal_volume
23pub_type
杂志文章abstract：:In this issue of Cell Chemical Biology,De Cesare et al. (2018) report the development of a high-throughput assay that measures E2/E3 enzyme activity by MALDI-TOF mass spectrometry and apply this to screen for small molecule E3 inhibitors. This assay potentially accelerates the drug discovery for the ubiquitin ligation...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2018.09.002
更新日期：2018-09-20 00:00:00
abstract：:USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.03.002
更新日期：2017-04-20 00:00:00
abstract：:Disease sites in atherosclerosis and cancer feature cell masses (e.g., plaques/tumors), a low pH extracellular microenvironment, and various pro-inflammatory cytokines such as tumor necrosis factor α (TNFα). The ability to engineer a cell to seek TNFα sources allows for targeted therapeutic delivery. To accomplish thi...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.05.008
更新日期：2017-06-22 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：:Small-molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind to and cleave RNA in a selective and substoichiometric manner. Here, we investigate the ability of RNA-targeted de...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.04.008
更新日期：2019-08-15 00:00:00
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
doi：10.1016/j.chembiol.2018.06.007
更新日期：2018-09-20 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：: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
更新日期：2019-10-17 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：:Interferon-induced transmembrane protein 3 (IFITM3) is a key interferon effector that broadly prevents infection by diverse viruses. However, the cellular factors that control IFITM3 homeostasis and antiviral activity have not been fully elucidated. Using site-specific photo-crosslinking and quantitative proteomic ana...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.03.004
更新日期：2020-05-21 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：:Rifamycin monooxygenases (Rox) are present in a variety of environmental bacteria and are associated with decomposition of the clinically utilized antibiotic rifampin. Here we report the structure and function of a drug-inducible rox gene from Streptomyces venezuelae, which encodes a class A flavoprotein monooxygenase...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.01.009
更新日期：2018-04-19 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：: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：:The Precision Medicine Initiative aims to use advances in basic and clinical research to develop therapeutics that selectively target and kill cancer cells. Under the same doctrine of precision medicine, there is an equally important need to visualize these diseased cells to enable diagnosis, facilitate surgical resec...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2015.12.003
更新日期：2016-01-21 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：: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：: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：:Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this comple...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.03.003
更新日期：2019-06-20 00:00:00
abstract：:Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a promising class of targeted cancer drugs, but their individual target profiles beyond the PARP family, which could result in differential clinical use or toxicity, are unknown. Using an unbiased, mass spectrometry-based chemical proteomics approach, we genera...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.10.011
更新日期：2016-12-22 00:00:00
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...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.11.001
更新日期：2020-11-19 00:00:00
abstract：:The rise of antibiotic resistance threatens modern medicine; to combat it new diagnostic methods are required. Sequencing the whole genome of a pathogen offers the potential to accurately determine which antibiotics will be effective to treat a patient. A key limitation of this approach is that it cannot classify rare...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.12.009
更新日期：2018-03-15 00:00:00
abstract：:Non-ribosomal peptides (NRPs) are biosynthesized on non-ribosomal peptides synthetase (NRPS) complexes, of which a C-terminal releasing domain commonly offloads the products. Interestingly, a dedicated releasing domain is absent in surugamides (SGM) NRPS, which directs the biosynthesis of cyclic octapeptides, SGM-A to...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.02.010
更新日期：2019-05-16 00:00:00
abstract：:Cryptochrome 1 (CRY1) and CRY2 are core regulators of the circadian clock, and the development of isoform-selective modulators is important for the elucidation of their redundant and distinct functions. Here, we report the identification and functional characterization of a small-molecule modulator of the mammalian ci...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.05.008
更新日期：2020-09-17 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：: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：:H2S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.10.012
更新日期：2020-12-17 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：: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：: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
