James E. Audia
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View article: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers
Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers Open
We report our mechanistic investigation into the conformationally-driven ‘activation bias’ of PPARG in muscle-invasive urothelial cancer (MIUC) and our efforts to pharmacologically reverse this activation bias through covalent PPARG invers…
Collaboration and knowledge integration for successful brain therapeutics – lessons learned from the pandemic Open
Brain diseases are a major cause of death and disability worldwide and contribute significantly to years of potential life lost. Although there have been considerable advances in biological mechanisms associated with brain disorders as wel…
GNE-064: A Potent, Selective, and Orally Bioavailable Chemical Probe for the Bromodomains of SMARCA2 and SMARCA4 and the Fifth Bromodomain of PBRM1 Open
Bromodomains are acetyllysine recognition domains present in a variety of human proteins. Bromodomains also bind small molecules that compete with acetyllysine, and therefore bromodomains have been targets for drug discovery efforts. Highl…
Ilaprazole and Other Novel Prazole-Based Compounds That Bind Tsg101 Inhibit Viral Budding of Herpes Simplex Virus 1 and 2 and Human Immunodeficiency Virus from Cells Open
These results provide the basis for the development of drugs that target enveloped virus budding that can be used ultimately to control multiple virus infections in humans.
Identification and characterization of second-generation EZH2 inhibitors with extended residence times and improved biological activity Open
The histone methyltransferase EZH2 has been the target of numerous small-molecule inhibitor discovery efforts over the last 10+ years. Emerging clinical data have provided early evidence for single agent activity with acceptable safety pro…
View article: The promise and peril of chemical probes
The promise and peril of chemical probes Open
Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-…
Design and Synthesis of Styrenylcyclopropylamine LSD1 Inhibitors Open
Leveraging the catalytic machinery of LSD1 (KDM1A), a series of covalent styrenylcyclopropane LSD1 inhibitors were identified. These inhibitors represent a new class of mechanism-based inhibitors that target and covalently label the FAD co…
Ilaprazole and other novel prazole-based compounds that bind Tsg101 inhibit viral budding of HSV-1/2 and HIV from cells Open
In many enveloped virus families, including HIV and HSV, a crucial, yet unexploited, step in the viral life cycle is releasing particles from the infected cell membranes. This release process is mediated by host ESCRT complex proteins, whi…
Design, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time Open
Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic ma…
Mentoring Matters in Drug Discovery Open
Mentoring is an essential opportunity to be embraced by medicinal chemists seeking a gratifying career. In this Viewpoint, we highlight the importance of developing an intentional mindset about mentoring to achieve professional goals. The …
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2) Open
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome…
Identification of (<i>R</i>)-<i>N</i>-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1<i>H</i>-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas Open
Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies an…
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains Open
The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand…
Histone Modifications and Cancer Open
Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable maintenance of repressive chromatin. In thi…
Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637) Open
CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targ…
Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials Open
In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of i…