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Here, we report the chemical proteomic discovery of electrophilic smallmolecules that stereoselectively and site-specifically bind the pioneer TF, FOXA1, at a cysteine (C258) within the forkhead DNA-binding domain. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells.
Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain.
A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. Rivers ACS Medicinal Chemistry Letters 2024 DOI: 10.1021/acsmedchemlett.4c00113
Also featured are the FKBP12 binding motif (light blue triangle), the DNA barcode (red double helix), and the combinatorial library element (red hexagon). Related groups Xavier lab Over the past two decades, large genetic studies have linked tens of thousands of DNA variants to thousands of human traits and diseases.
There is extensive crosstalk between the DNA damage response (DDR) and innate immune pathways. Both are a focus for exciting new small-molecule drug therapeutics that target cancers and autoimmune disorders.
Abstract Proliferating cell nuclear antigen (PCNA) is a homo-trimeric protein complex that clamps around DNA to tether DNA polymerases to the template during replication and serves as a hub for many other interacting proteins. The assay design is to discover bioactive smallmolecules that restore proliferation in T. brucei
Despite the current hype around so called “advanced therapies”, which range from gene editing to cell therapies, and the inexorable advance of biologic therapeutics such as monoclonal antibodies, even in 2022 the majority of drugs in development and reaching patients are still small organic molecules.
Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all 12 human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts.
Covalent ligands are a promising strategy to pharmacologically target nuclear proteins, such as transcription factors, which lack ordered small-molecule binding pockets. To identify nuclear cysteines that are susceptible to covalent liganding, we couple proximity labeling (PL), using a histone H3.3-TurboID
We further show that members of our nucleophilic fragment library can impair functional protein–protein interactions involved in nuclear oncoprotein transport and DNA damage repair.
The bulk of my nearly three decades of experience up to that point was with drugging protein targets using a variety of modalities, but principally smallmolecules. And unproductive interactions between the RNA target and the DNA barcodes complicated DEL screening. Screening to Set a Course Screening brings its own challenges.
For both cancer and healthy genomes, we find that cysteine acquisition is a ubiquitous consequence of genetic variation that is further elevated in the context of decreased DNA repair.
By training PLACER on structures stored in the Protein Data Bank, the team taught the model to predict atom arrangements that follow the physical and chemical rules governing protein-smallmolecule interactions. They synthesized DNA encoding each protein variant, expressed the proteins in E.
researching DNA photoproducts related to skin cancer. As the ADC team moved toward a greater emphasis on development, Dian felt the pull to return to her “research mindset” and switched paths again, this time delving into DMPK, particularly smallmolecules and peptides. “I Proteomics!
Technologies for the rapid and efficient testing of smallmolecules and biologics have greatly accelerated drug discovery. Intermediate-sized molecules such as macrocycles combining the beneficial properties of both smallmolecules and biologics may enable the targeting of currently undruggable targets.
These multifunctional smallmolecules are like tiny spies, hijacking the body’s natural protein degradation system to remove unwanted proteins. Multifunctional SmallMolecules and Peptides Beyond PROTACs, there are other exciting tools in the new drug discovery toolbox.
One approach is to look beyond the traditional drug molecule. Researchers are experimenting with biologics—larger biological molecules that can do things smallmolecules can't, like targeting larger, more complex structures on cell surfaces or even inside cells.
Instead of the black, printed stripes of the Universal Product Codes (UPCs) that we see on everything from package deliveries to clothing tags, they used short, unique snippets of DNA to label cells. DNA barcoding has already empowered single-cell analysis, including for nerve cells in the brain. PRISM consists of two key components.
Finding smallmolecule drugs is much harder than finding a needle in a haystack – discovering the right arrangement of atoms to bind precisely to a protein target to elicit a particular response is a problem of vast dimensionality. Yet the situation with smallmolecules is even worse.
Molecular dynamics (MD) simulations and other computational methods are vital tools in our arsenal , helping us peek into the atomic-level interactions and movements within the protein, helping reveal potential new binding sites induced by smallmolecule interactions. DNA and RNA are also key players, each bringing unique challenges.
2 In response, DNA-damaging agents that could target the entire cell cycle received renewed attention as ADC payloads. Groundbreaking strategies like proteolysis-targeting chimeric molecules (PROTACs) are also being explored. DNA damaging agent-based antibody-drug conjugates for cancer therapy. Florian S, Mitchison TJ.
Gleevec is a smallmolecule that interferes with entry of an enzyme – a tyrosine kinase – that enables growth signals to enter specific cells and trigger division. A name ending in “nib” means a smallmolecule that inhibits an enzyme called a kinase, and is short for “inhibit.”
Allison Berke makes the case for real-time DNA sequencing and AI tools to detect pathogens before they spread widely. Reading DNA The first step in detecting a novel pathogen is recognizing it as an anomaly amidst a noisy background of other material. After copying the DNA to form a big pool, each piece is sequenced.
For my PhD project, I chose an advisor who worked on DNA and I started working with her on the physical properties of DNA. I worked with Jackie Barton in the early days of what’s now called DNA-mediated electron transfer. And that was a very controversial idea. And my answer to that has changed over the years.
And unlike traditional DNA sequencers, which parse genetic material by breaking it up into fragments and interpreting it chunk-by-chunk, a nanopore device unspools a long strand of DNA and reads it all at once. A scientist can isolate DNA and load up a flow cell in fifteen minutes. Nanopore devices work incredibly fast.
These regimens frequently include one or two smallmolecule inhibitors and immuno-oncology (IO) therapies, such as monoclonal antibodies and T-cell engagers. To bring us closer to curing cancer, a combination of effective drugs with non-overlapping mechanisms of action is required.
Durham, North Carolina-based Ribometrix announced a strategic collaboration deal with Genentech , a Roche company, to identify and advance novel RNA-targeted smallmolecule therapeutics. This is because many proteins do not have small-molecule binding sites. This is not the first deal for RNA therapeutics for Genentech.
Drugs that treat symptoms in other HSP types could inform treatments for similar symptoms in KAND, so we’re always on the lookout for smallmolecule or technological interventions that work in other SPGs. Simran Kaur’s 2023 conference talk briefly describes the KIF1A mini-gene approach.
Our in-house SPR equipment comprises: 2x Biacore TM 8K+ 3x Biacore TM 8K 1x Biacore TM T200 This covers mM binders, such as fragments, through to sub pM interactions (such as late stage smallmolecules or very high affinity biological interactions, Tollenaere et al 2023 [link] ). This technology measures affinities from mM to nM.
The other powerful benefit is that our cell lines can become any of the cell types of the human body – these cells have within their DNA the capability to become any of the more than 200 human cell types which you might want to manufacture. Just like smallmolecules and antibodies, cell therapies are changing how we treat patients.
The majority of smallmolecule drugs induce their therapeutic effects by seeking out and binding to their intended target while avoiding most other molecules in the dense milieu of the cell interior. Our overall mission at Arrakis is to expand the set of “druggable” targets for small-molecule medicines to include RNA.
link] 01 Aug 2022 Cortexyme is now called Quince Therapeutics You need to be a logged in or subscribed to view this content This smallmolecule is an orally available protease inhibitor targeting the lysine proteases of the periodontal pathogen Porphyromonas gingivalis. gingivalis DNA fragments in their CSF at baseline.
In an infected animal, cGAS senses viral DNA in cytoplasm whilst in an uninfected organism, DNA is confined in the nucleus. Bacteria must take a different approach as they do not have nuclei and if CBASS reacted to the presence of DNA, it would cause autoimmunity or the bacterium to attack itself, Banh said. But what, exactly?”
New supercomputing-scale large language models (LLMs) that understand biology and chemistry text are helping scientists understand proteins, smallmolecules, DNA, and biomedical text. These state-of-the-art AI models help generate de novo proteins and molecules and predict the 3D structures of proteins.
We believe liquid biopsy is very helpful for oncology drug development because the reduction and clearance of circulating DNA occurs quickly before radiographic imaging is available. The initial techniques were able to detect circulating tumour DNA in patients who already had metastatic spread.
As soon as I learned about DNA and RNA, I wanted to be a molecular biologist. Last stops at RNA My last roles in biotech were where my original passion began: DNA and RNA. My last stop at Arrakis Therapeutics is with a company targeting RNA with smallmolecules. I wanted to use molecular biology to create drugs.
During the development of new smallmolecule drug products, developers must conduct impurity and degradant evaluation at several points in the program and to varying degrees. In addition, this guidance focuses on DNA reactive substances that could potentially cause cancer. Global regulatory agencies, including the U.S.
The genomic capabilities that were brought online for drug discovery (cheaper & faster next-gen DNA sequencing) did not diminish the need for biologists and translational scientists in target and patient selection, respectively. One final parallel to 2001.
DNA and RNA molecules are also built from exclusively right-handed nucleic acids. Glucose is a chiral molecule because its structure allows for two distinct configurations, or enantiomers, which cannot be superimposed on each other. The mirrored enzyme seamlessly transcribed 2,900 bases of mirrored DNA into mirrored RNA.
Trapping agents are described for reactive metabolites that could ordinarily be overlooked due to quenching with endogenous smallmolecules and protein nucleophiles.
These hair clip-like molecules clamp onto DNA, thereby turning many genes on and off. As Darnell observed, the prospect of being able to regulate Transcription Factor function holds the potential to reframe the way we treat disease but achieving that goal with traditional smallmolecule screening approaches is impossible.
Broadens company’s oncology platform of Targeted Alpha Therapies / Acquisition includes actinium-225 labeled differentiated PSMA smallmolecule for the treatment of prostate cancer. It has been demonstrated to inflict difficult to repair damage to tumor cells by inducing DNA double strand breaks.
Through the acquisition, Gilead gains rights to a portfolio of smallmolecule inhibitors targeting PARP1 for oncology and MK2 for inflammatory diseases that could enter clinical trials later this year. Executive Vice President, Research, Gilead Sciences. The company was founded in 2021 by Stephen Kaldor, Ph.D., Qing Dong, Ph.D.,
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