Abstract:
:There is a current and pressing need for improved cancer therapies. The use of small molecule kinase inhibitors and their application in combinatorial regimens represent an approach to personalized targeted cancer therapy. A number of AGC kinases, including atypical Protein Kinase C enzymes (PKCs), are validated drug targets for cancer treatment. Most drug development programs for protein kinases focus on the development of drugs that bind at the ATP-binding site. Alternatively, allosteric drugs have great potential for the development of future innovative drugs. However, the rational development of allosteric drugs poses important challenges because the compounds not only must bind to a given site but also must stabilize forms of the protein with a desired effect at a distant site. Here we describe the development of a new class of compounds targeting a regulatory site (PIF-pocket) present in the kinase domain and provide biochemical and crystallographic data showing that these compounds allosterically inhibit the activity of atypical PKCs. PS432, a representative compound, decreased the rate of proliferation of non-small cell lung cancer cells more potently than aurothiomalate, an atypical PKCι inhibitor currently under evaluation in clinical trials, and significantly reduced tumor growth without side effects in a mouse xenograft model. The druglike chemical class provides ample possibilities for the synthesis of derivative compounds, with the potential to allosterically modulate the activity of atypical PKCs and other kinases.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Arencibia JM,Fröhner W,Krupa M,Pastor-Flores D,Merker P,Oellerich T,Neimanis S,Schmithals C,Köberle V,Süß E,Zeuzem S,Stark H,Piiper A,Odadzic D,Schulze JO,Biondi RMdoi
10.1021/acschembio.6b00827subject
Has Abstractpub_date
2017-02-17 00:00:00pages
564-573issue
2eissn
1554-8929issn
1554-8937journal_volume
12pub_type
杂志文章abstract::Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specif...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00562
更新日期:2018-09-21 00:00:00
abstract::SGK3 is a PX domain containing protein kinase activated at endosomes downstream of class 1 and 3 PI3K family members by growth factors and oncogenic mutations. SGK3 plays a key role in mediating resistance of breast cancer cells to class 1 PI3K or Akt inhibitors, by substituting for the loss of Akt activity and restor...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.9b00505
更新日期:2019-09-20 00:00:00
abstract::Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω-alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lip...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00480
更新日期:2017-08-18 00:00:00
abstract::Phenotypic screening of compound libraries is a significant trend in drug discovery, yet success can be hindered by difficulties in identifying the underlying cellular targets. Current approaches rely on tethering bioactive compounds to a capture tag or surface to allow selective enrichment of interacting proteins for...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00351
更新日期:2015-10-16 00:00:00
abstract::Enzymatic plasticity, as a modern term referring to the functional conversion of an enzyme, is significant for enzymatic activity redesign. The bacterial diterpene cyclase CotB2 is a typical plastic enzyme by which its native form precisely conducts a chemical reaction while its mutants diversify the catalytic functio...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00645
更新日期:2020-10-16 00:00:00
abstract::The display and analysis of proteins expressed on biological surfaces has become an attractive tool for the study of molecular interactions in enzymology, protein engineering, and high-throughput screening. Among the growing number of established display systems, retroviruses offer a unique and fully mammalian platfor...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb100285n
更新日期:2011-01-21 00:00:00
abstract::The ubiquity of microorganisms is unparalleled in any other known organism. These creatures surround our outsides and colonize our insides, a fact that has been known for centuries. However, despite their prevalence and long study, many of their characteristics still remain largely unexplained, including how proteins ...
journal_title:ACS chemical biology
pub_type: 传,历史文章,杂志文章
doi:10.1021/cb100179t
更新日期:2010-07-16 00:00:00
abstract::Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00056
更新日期:2017-05-19 00:00:00
abstract::Peptidoglycan glycosyltransferases (PGTs), enzymes that catalyze the formation of the glycan chains of the bacterial cell wall, have tremendous potential as antibiotic targets. The moenomycins, a potent family of natural product antibiotics, are the only known active site inhibitors of the PGTs and serve as blueprints...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb800078a
更新日期:2008-07-18 00:00:00
abstract::Understanding the ways in which pathogens invade and neutralize their hosts is of great interest from both an academic and a clinical perspective. However, in many cases genetic tools are unavailable or insufficient to fully characterize the detailed mechanisms of pathogenesis. Small molecule approaches are particular...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb9001409
更新日期:2009-08-21 00:00:00
abstract::N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b00913
更新日期:2017-02-17 00:00:00
abstract::RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is bel...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb4001553
更新日期:2013-07-19 00:00:00
abstract::Cysteine residues on proteins play key roles in catalysis and regulation. These functional cysteines serve as active sites for nucleophilic and redox catalysis, sites of allosteric regulation, and metal-binding ligands on proteins from diverse classes including proteases, kinases, metabolic enzymes, and transcription ...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb3005269
更新日期:2013-02-15 00:00:00
abstract::MbtA is an adenylating enzyme from Mycobacterium tuberculosis that catalyzes the first step in the biosynthesis of the mycobactins. A bisubstrate inhibitor of MbtA (Sal-AMS) was previously described that displays potent antitubercular activity under iron-replete as well as iron-deficient growth conditions. This findin...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300112x
更新日期:2012-10-19 00:00:00
abstract::Cell-penetrating peptides (CPPs) are capable of delivering membrane-impermeable cargoes (including small molecules, peptides, proteins, nucleic acids, and nanoparticles) into the cytosol of mammalian cells and have the potential to revolutionize biomedical research and drug discovery. However, the mechanism of action ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00478
更新日期:2020-09-18 00:00:00
abstract::Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Gα-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb400568g
更新日期:2013-12-20 00:00:00
abstract::Generating highly selective probes to interrogate protein kinase function in biological studies remains a challenge, and new strategies are required. Herein, we describe the development of the first highly selective and cell-permeable inhibitor of c-Src, a key signaling kinase in cancer. Our strategy involves extensio...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300172e
更新日期:2012-08-17 00:00:00
abstract::Lysine specific demethylase 1 (LSD1, also known as KDM1) is a histone modifying enzyme that regulates the expression of many genes important in cancer progression and proliferation. It is present in various transcriptional complexes including those containing the estrogen receptor (ER). Indeed, inhibition of LSD1 acti...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb300108c
更新日期:2012-07-20 00:00:00
abstract::The genetic integrity of each organism depends on the faithful segregation of its genome during mitosis. To meet this challenge, a cellular surveillance mechanism, termed the spindle assembly checkpoint (SAC), evolved that monitors the correct attachment of chromosomes and blocks progression through mitosis if correct...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00121
更新日期:2015-07-17 00:00:00
abstract::The quest for ever more selective kinase inhibitors as potential future drugs has yielded a large repertoire of chemical probes that are selective for specific kinase conformations. These probes have been useful tools to obtain structural snapshots of kinase conformational plasticity. Similarly, kinetic and thermodyna...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb500870a
更新日期:2015-01-16 00:00:00
abstract::Protein arginine N-methyltransferase 3 (PRMT3) belongs to the family of type I PRMTs and harbors the activity to use S-adenosyl-l-methionine (SAM) as a methyl-donor cofactor for protein arginine labeling. However, PRMT3's functions remain elusive with the lacked knowledge of its target scope in cellular settings. Insp...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb4008259
更新日期:2014-02-21 00:00:00
abstract::A two-way colorimetric biosensor based on unmodified gold nanoparticles (GNPs) and a switchable double-stranded DNA (dsDNA) concatemer have been demonstrated. Two hairpin probes (H1 and H2) were first designed that provided the fuels to assemble the dsDNA concatemers via hybridization chain reaction (HCR). A functiona...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00060
更新日期:2017-05-19 00:00:00
abstract::Tumor heterogeneity has hampered the development of novel effective therapeutic options for aggressive cancers, including the deadly primary adult brain tumor glioblastoma (GBM). Intratumoral heterogeneity is partially attributed to the tumor initiating cell (TIC) subset that contains highly tumorigenic, stem-like cel...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00251
更新日期:2018-08-17 00:00:00
abstract::Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other relate...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb800039y
更新日期:2008-05-16 00:00:00
abstract::Nephronectin is an extracellular matrix protein that interacts with the α8β1 integrin receptor and plays a role in tissue and organ development, though the motifs that mediate adhesion to the receptor remain unclear. This paper describes the use of self-assembled monolayers to study the adhesion of α8β1-presenting cel...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200186j
更新日期:2011-10-21 00:00:00
abstract::The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant toward small molecule inhibition despite ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b00751
更新日期:2017-01-20 00:00:00
abstract::Lanthipeptides are ribosomally synthesized and post-translationally modified peptides bearing the characteristic amino acids lanthionine and/or labionin. Here, we report on the discovery and characterization of the stackepeptins, produced by the Actinomycete Stackebrandtia nassauensis DSM-44728(T). The stackepeptins a...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00651
更新日期:2016-01-15 00:00:00
abstract::Leishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mecha...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00972
更新日期:2019-02-15 00:00:00
abstract::Acute and specific sensing of diatomic gas molecules is an essential facet of biological signaling. Heme nitric oxide/oxygen binding (H-NOX) proteins are a family of gas sensors found in diverse classes of bacteria and eukaryotes. The most commonly characterized bacterial H-NOX domains are from facultative anaerobes a...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.6b00431
更新日期:2016-08-19 00:00:00
abstract::ABCG2 is a membrane-localized, human transporter protein that has been demonstrated to reduce the intracellular accumulation of substrates through ATP-dependent efflux. Highly expressed in placental syncytiotrophoblasts, brain microvasculature, and the gastrointestinal tract, ABCG2 has been shown to mediate normal tis...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb900134c
更新日期:2009-08-21 00:00:00