Abstract:
:Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting temperature of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small molecule ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine-protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole ethyl anchor, which is deeply buried within the binding site in the Y220C-PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol(-1) atom(-1)). High-resolution crystal structures of the Y220C-ligand complexes combined with quantum chemical calculations revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein-fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Bauer MR,Jones RN,Baud MG,Wilcken R,Boeckler FM,Fersht AR,Joerger AC,Spencer Jdoi
10.1021/acschembio.6b00315subject
Has Abstractpub_date
2016-08-19 00:00:00pages
2265-74issue
8eissn
1554-8929issn
1554-8937journal_volume
11pub_type
杂志文章abstract::Current therapeutic interventions for both heart disease and heart failure are largely insufficient and associated with undesired side effects. Biomedical research has emphasized the role of sarcomeric protein function for the normal performance and energy efficiency of the heart, suggesting that directly targeting th...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00908
更新日期:2021-01-15 00:00:00
abstract::RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) that form a complex involved in a variety of cellular processes, including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated with tumor growth and poor pro...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00904
更新日期:2019-02-15 00:00:00
abstract::There is increasing concern that animal and human reproduction may be adversely affected by exposure to xenoestrogens that activate estrogen receptors. There is evidence that one such compound, Bisphenol A (BPA), also induces meiotic and mitotic aneuploidy, suggesting that these kinds of molecules may also have effect...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb700210u
更新日期:2008-03-20 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::A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a cha...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb4005832
更新日期:2013-10-18 00:00:00
abstract::We recently reported two novel tools for precisely controlling and quantifying Cas9 activity: a chemically inducible Cas9 variant (ciCas9) that can be rapidly activated by small molecules and a ddPCR assay for time-resolved measurement of DNA double strand breaks (DSB-ddPCR). Here, we further demonstrate the potential...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b00652
更新日期:2018-02-16 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::Terpenes are ubiquitous natural chemicals with diverse biological functions spanning all three domains of life. In specialized metabolism, the active sites of terpene synthases (TPSs) evolve in shape and reactivity to direct the biosynthesis of a myriad of chemotypes for organismal fitness. As most terpene biosynthesi...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00539
更新日期:2015-11-20 00:00:00
abstract::Pyrrole-imidazole alkaloids are natural products isolated from marine sponges, holobiont metazoans that are associated with symbiotic microbiomes. Pyrrole-imidazole alkaloids have attracted attention due to their chemical complexity and their favorable pharmacological properties. However, insights into how these molec...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00375
更新日期:2020-08-21 00:00:00
abstract::Regulation of gene expression by RNA processing mechanisms is now understood to be an important level of control in mammalian cells. Regulation at the level of RNA transcription, splicing, polyadenylation, nucleo-cytoplasmic transport, and translation into polypeptides has been well-studied. Alternative RNA processing...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb800138w
更新日期:2008-10-17 00:00:00
abstract::Hemolysis, a process by which the destruction of red blood cells leads to the release of hemoglobin, is a critical event observed during hemolytic disorders. Under oxidative stress conditions, hemoglobin can release its heme prosthetic group, which is highly cytotoxic and can catalyze the generation of reactive oxygen...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00458
更新日期:2018-08-17 00:00:00
abstract::Apicomplexan parasites, including Plasmodium falciparum and Toxoplasma gondii, the causative agents of severe malaria and toxoplasmosis, respectively, undergo several critical developmental transitions during their lifecycle. Most important for human pathogenesis is the asexual cycle, in which parasites undergo rounds...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb501004q
更新日期:2015-04-17 00:00:00
abstract::Ammonia lyases catalyze the formation of α,β-unsaturated bonds by the elimination of ammonia from their substrates. This conceptually straightforward reaction has been the emphasis of many studies, with the main focus on the catalytic mechanism of these enzymes and/or the use of these enzymes as catalysts for the synt...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb3002792
更新日期:2012-10-19 00:00:00
abstract::Large-scale quantification of protein O-linked β- N-acetylglucosamine (O-GlcNAc) modification in a site-specific manner remains a key challenge in studying O-GlcNAc biology. Herein, we developed an isotope-tagged cleavable linker (isoTCL) strategy, which enabled isotopic labeling of O-GlcNAc through bioorthogonal conj...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.8b00414
更新日期:2018-08-17 00:00:00
abstract::Dicamba monooxygenase (DMO) catalyzes the O-demethylation of dicamba (3,6-dichloro-2-methoxybenzoate) to produce 3,6-dichlorosalicylate and formaldehyde. Recent crystallographic studies suggest that DMO catalyzes the challenging oxidation of a saturated C-H bond within the methyl group of dicamba to form a hemiacetal ...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb400154a
更新日期:2013-08-16 00:00:00
abstract::Synthetic biology is the realization of systems with desired behavior using biological materials. A recent addition to the field is a bipartite consortium of the bacterium Escherichia coli in which each species harbors complementary gene circuits that actuate only when both are present above a critical density. This b...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb700256w
更新日期:2008-01-18 00:00:00
abstract::Albicidin is a potent antibiotic and phytotoxin produced by Xanthomonas albilineans which targets the plant and bacterial DNA gyrase. We now report on a new albicidin derivative which is carbamoylated at the N-terminal coumaric acid by the action of the ATP-dependent O-carbamoyltransferase Alb15, present in the albici...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b01001
更新日期:2016-05-20 00:00:00
abstract::Aminoglycoside antibiotics were among the first antibiotics discovered and used clinically. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections ca...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb3005116
更新日期:2013-01-18 00:00:00
abstract::A complication of diabetes is the inability of wounds to heal in diabetic patients. Diabetic wounds are refractory to healing due to the involvement of activated matrix metalloproteinases (MMPs), which remodel the tissue resulting in apoptosis. There are no readily available methods that identify active unregulated MM...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb4005468
更新日期:2014-01-17 00:00:00
abstract::Simocyclinone D8 (1, SD8) has attracted attention due to its highly complex hybrid structure and the unusual way it inhibits bacterial DNA gyrase by preventing DNA binding to the enzyme. Although a hypothesis explaining simocyclinone biosynthesis has been previously proposed, little was proven in vivo due to the genet...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00669
更新日期:2016-01-15 00:00:00
abstract::Small molecule kinase inhibitors that stabilize distinct ATP binding site conformations can differentially modulate the global conformation of Src-family kinases (SFKs). However, it is unclear which specific ATP binding site contacts are responsible for modulating the global conformation of SFKs and whether these inhi...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.0c00429
更新日期:2020-07-17 00:00:00
abstract::Epigenetic regulation of gene expression is essential in many biological processes, and its deregulation contributes to pathology including tumor formation. We used an image-based cell assay that measures the induction of a silenced GFP-estrogen receptor reporter to identify novel classes of small molecules involved i...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb500532x
更新日期:2014-11-21 00:00:00
abstract::Dihydrofolate reductase (DHFR) is a potential drug target for Trypanosoma brucei, a human parasite, which is the causative agent for African sleeping sickness. No drug is available against this target, since none of the classical antifolates such as pyrimethamine (PYR), cycloguanil, or trimethoprim are effective as se...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb200124r
更新日期:2011-09-16 00:00:00
abstract::Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rat...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb600276q
更新日期:2006-09-19 00:00:00
abstract::This report highlights the advantages of low-affinity, multivalent interactions to recognize one cell type over another. Our goal was to devise a strategy to mediate selective killing of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. To test wh...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/cb6003788
更新日期:2007-02-20 00:00:00
abstract::Chloropupukeananin and chloropestolides are novel metabolites of the plant endophyte Pestalotiopsis fici, showing antimicrobial, antitumor, and anti-HIV activities. Their highly complex and unique skeletons were generated from the coisolated pestheic acid (1) and iso-A82775C (10) based on our previous studies. Here, w...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.7b01059
更新日期:2018-03-16 00:00:00
abstract::Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of cysteine or serine side chains, this aldehyde-functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester...
journal_title:ACS chemical biology
pub_type: 杂志文章,评审
doi:10.1021/cb500897w
更新日期:2015-01-16 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::Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly conver...
journal_title:ACS chemical biology
pub_type: 信件
doi:10.1021/acschembio.8b00981
更新日期:2019-02-15 00:00:00
abstract::Novel strategies are needed to modulate β-cell differentiation and function as potential β-cell replacement or restorative therapies for diabetes. We previously demonstrated that small molecules based on the isoxazole scaffold drive neuroendocrine phenotypes. The nature of the effects of isoxazole compounds on β-cells...
journal_title:ACS chemical biology
pub_type: 杂志文章
doi:10.1021/acschembio.5b00993
更新日期:2016-04-15 00:00:00