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Redirecting the pioneering function of FOXA1 with covalent small molecules

Covalent Modifiers

Here, we report the chemical proteomic discovery of electrophilic small molecules 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.

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Redirecting the pioneering function of FOXA1 with covalent small molecules

Covalent Modifiers

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.

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Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen

Covalent Modifiers

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

DNA 182
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Researchers devise new way to target and correct disease-related proteins

Broad Institute

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.

Disease 139
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A Guide to DNA Damage Response and Innate Immunity

Drug Target Review

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.

DNA 104
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A phenotypic screen with Trypanosoma brucei for discovering small molecules that target the SLiM?binding pocket of proliferating cell nuclear antigen orthologs

Chemical Biology and Drug Design

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 small molecules that restore proliferation in T. brucei

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How to find a drug: the past, present and future of small molecule drug discovery?

DrugBaron

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.