The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation, we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors.
View Article and Find Full Text PDFFluorinated breakdown products from photolysis of pharmaceuticals and pesticides are of environmental concern due to their potential persistence and toxicity. While mass spectrometry workflows have been shown to be useful in identifying products, they fall short for fluorinated products and may miss up to 90% of products. Studies have shown that F NMR measurements assist in identifying and quantifying reaction products, but this protocol can be further developed by incorporating computations.
View Article and Find Full Text PDFThe design of imaging agents with a high fluorine content is necessary for overcoming the challenges of low sensitivity in F magnetic resonance imaging (MRI)-based molecular imaging. Chemically self-assembled nanorings (CSANs) provide a strategy to increase the fluorine content through multivalent display. We previously reported an F NMR-based imaging tracer, in which case a CSAN-compatible epidermal growth factor receptor (EGFR)-targeting protein E-dimeric dihydrofolate (E-DD) was bioconjugated to a highly fluorinated peptide.
View Article and Find Full Text PDFMethyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter targeting PHD fingers exists.
View Article and Find Full Text PDFPeptide-based therapeutics have gained attention as promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. In this paper, we report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine SAr chemistry, with decafluoro-diphenylsulfone (DFS). Testing of the binding of the selected peptides to albumin identified SICRFFC as the lead sequence.
View Article and Find Full Text PDFNatural products are often uniquely suited to modulate protein-protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (K 1 μM) with a non-canonical binding site containing a structurally dynamic loop in CBP/p300 KIX.
View Article and Find Full Text PDFThe design of imaging agents with high fluorine content is essential for overcoming the challenges associated with signal detection limits in F MRI-based molecular imaging. In addition to perfluorocarbon and fluorinated polymers, fluorinated peptides offer an additional strategy for creating sequence-defined F magnetic resonance imaging (MRI) imaging agents with a high fluorine signal. Our previously reported unstructured trifluoroacetyllysine-based peptides possessed good physiochemical properties and could be imaged at high magnetic field strength.
View Article and Find Full Text PDFTargeted protein degradation is an emerging technology that can be used for modulating the activity of epigenetic protein targets. Among bromodomain-containing proteins, a number of degraders for the BET family have been developed, while non-BET bromodomains remain underexplored. Several of these proteins are subunits in chromatin remodeling complexes often associated with oncogenic roles.
View Article and Find Full Text PDFCurrent experiments that rely on biosynthetic metabolic protein labeling with F often require fluorinated amino acids, which in the case of 2- and 3-fluorotyrosine can be expensive. However, using these amino acids has provided valuable insight into protein dynamics, structure, and function. Here, we develop a new in-cell method for fluorinated tyrosine generation from readily available substituted phenols and subsequent metabolic labeling of proteins in a single bacterial expression culture.
View Article and Find Full Text PDFThe type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors.
View Article and Find Full Text PDFAccurate temperature measurement via magnetic resonance is valuable for both and analysis of local tissue for evaluating disease pathology and medical interventions. H MRI-based thermometry is used clinically but is susceptible to error from magnetic field drift and low sensitivity in fatty tissue and requires a reference for absolute temperature determination. As an alternative, perfluorotributylamine (PFTBA), a perfluorocarbon liquid for F MRI thermometry, is based on chemical shift responsiveness and approaches the sensitivity of H MRI thermometry agents; however, environmental persistence, greenhouse gas concerns, and multiple resonances which can lead to MRI artifacts indicate a need for alternative sensors.
View Article and Find Full Text PDFEpigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine-ε-N-acetylation (K ), bromodomains serve as recognition modules ("readers") of this activating epigenetic mark and competition of the bromodomain-K interaction with small-molecule inhibitors is an attractive strategy to control aberrant bromodomain-mediated gene expression.
View Article and Find Full Text PDFThe wavelength dependence of photoproduct formation and quantum yields was evaluated for fluorinated pesticides and pharmaceuticals using UV-light emitting diodes (LEDs) with 255, 275, 308, 365, and 405 nm peak wavelengths. The fluorinated compounds chosen were saflufenacil, penoxsulam, sulfoxaflor, fluoxetine, 4-nitro-3-trifluoromethylphenol (TFM), florasulam, voriconazole, and favipiravir, covering key fluorine motifs (benzylic-CF, heteroaromatic-CF, aryl-F, and heteroaromatic-F). Quantum yields for the compounds were consistently higher for UV-C as compared to UV-A wavelengths and did not show the same trend as molar absorptivity.
View Article and Find Full Text PDFH,N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically disordered monomeric α-Synuclein (aSyn). We report how solution pH can impact the interpretation of aSyn HSQC NMR spectra and demonstrate that small-molecule formulations (e.g.
View Article and Find Full Text PDFTargeted protein degradation is a powerful induced-proximity tool to control cellular protein concentrations using small molecules. However, the design of selective degraders remains empirical. Among bromodomain and extra-terminal (BET) family proteins, BRD4 is the primary therapeutic target over family members BRD2/3/T.
View Article and Find Full Text PDFEnviron Sci Technol
September 2022
The photolysis of pesticides with different fluorine motifs was evaluated to quantify the formation of fluorinated products in buffered aqueous systems, advanced oxidation (AOP) and reduction processes (ARP), and river water. Simulated sunlight quantum yields at pH 7 were 0.0033, 0.
View Article and Find Full Text PDFEpigenetic reader domains regulate chromatin structure and modulate gene expression through the recognition of post-translational modifications on histones. Recently, reader domains have also been found to harbor double-stranded (ds) DNA-binding activity, which is as functionally critical as histone association. Here, we explore the dsDNA recognition of the N-terminal bromodomain of the bromodomain and extra-terminal (BET) protein, BRD4.
View Article and Find Full Text PDFInnovation in medicinal chemistry has been at the heart of since the journal's founding 10 years ago. In his inaugural editorial, Editor-in-Chief Dennis Liotta laid out a vision for the journal to become the "premier international journal for rapid communication of cutting-edge studies," and, after 10 years, it has become exactly that. The great hope of drug discovery scientists is that their innovations will lead to new therapeutics to treat unmet medical needs.
View Article and Find Full Text PDFTemperature can affect many biological and chemical processes within a body. During measurements, varied temperature can impact the accurate quantification of additional abiotic factors such as oxygen. During magnetic resonance imaging (MRI) measurements, the temperature of the sample can increase with the absorption of radiofrequency energy, which needs to be well-regulated for thermal therapies and long exposure.
View Article and Find Full Text PDFFluorine incorporation into organic molecules has increased due to desirable changes in the molecular physiochemical properties. Common fluorine motifs include: aliphatic fluorines and -CF, or -F containing groups bonded directly onto an aromatic (Ar-CF and Ar-F) or heteroaromatic ring. Photolysis of these compounds, either in natural or engineered systems, is a potential source of new fluorinated byproducts.
View Article and Find Full Text PDFChemical probes for epigenetic proteins are essential tools for dissecting the molecular mechanisms for gene regulation and therapeutic development. The bromodomain and extra-terminal (BET) proteins are master transcriptional regulators. Despite promising therapeutic targets, selective small molecule inhibitors for a single bromodomain remain an unmet goal due to their high sequence similarity.
View Article and Find Full Text PDF© LitMetric 2025. All rights reserved.