Phoebe
Rubio
Development of a Small-Molecule Inhibitor for USP48
Abstract profile. Full document pending author claim.
Authors:
Phoebe Rubio, Michael Darnowski, Sara Buhrlage
Date Created:
2025-01-01
Course Title:
Professor:
Not specified
About Paper:
Acute myeloid leukemia (AML) is an aggressive cancer with a (SAR) studies by derivatizing the compounds using multi-step poor prognosis. Since nearly half of AML patients have mutations synthesis. We introduced both conservative and more dramatic in DNA methylation-related genes, DNA hypomethylating agents modificationstomultiplemodifiableregions,adjustingthesizeand (HMAs) are commonly used as treatment. However, HMAs alone polarityofitssidegroupswhilepreservingthecorescaffold. These show limited success, driving interest in combination therapies changes allow us to better understand which chemical features are to improve outcomes. To identify the genetic drivers of HMA criticalforactivityandhelpguidethedevelopmentofamorepotent sensitivity, our collaborator, Dr. Kim Stegmaier, conducted analog. To evaluate inhibition of USP48 by the new compounds, a CRISPR-Cas9 screen and found that the knockout of the we use a high-throughput, fluorescence-based biochemical assay deubiquitinating enzyme USP48 sensitized AML cells to HMAs. that employs ubiquitin-rhodamine as substrate, which enables As deubiquitinases (DUBs) remove ubiquitin tags from target quantitative measurement of inhibitor potency. Results from proteins and thus regulate protein stability, they are compelling these assays direct the structural design of additional analogs to therapeutic targets due to their essential cellular roles. These enhance the inhibitor. Once optimized, we intend to perform findings prompted us to develop a novel small molecule inhibitor site-directed mutagenesis to identify critical binding residues and of USP48. To pursue this, the Buhrlage lab screened over 75,000 further characterize the interaction, and investigate the effects of small molecule compounds and identified promising scaffolds pharmacological inhibition of USP48 in combination with HMAs with selectivity for USP48. Building on one of these initial in preclinical models. Ultimately, we hope this new combination hit compounds, I performed initial structure-activity-relationship will improve outcomes for patients with AML. TheRoleofFollicle-StimulatingHormone(FSH)inSkeletalMuscleLossPost- Menopause Jerome Jarjoura, Tyler McNeill, Fabrisia Ambrosio University of Tennessee Knoxville | Human Developmental and Regenerative Biology | 2026 Menopause, typically occurring around age 50, marks the end of a hypothalamic-pituitaryaxisalsoleadstoelevatedlevelsoffollicle- woman’s reproductive years and is associated with an increased stimulating hormone (FSH). The role of FSH in skeletal muscle risk of various chronic diseases. Despite these sex-specific decline, however, remains poorly understood. changes, aging research has historically relied on male preclinical models, and existing female models fail to replicate the complex Toaddressthisgap, wecompareskeletalmuscleinovariectomized hormonal landscape of human menopause. The goal of our work (OVX) female mice – a model of menopause – with that of OVX mice treated with an FSH-inhibiting antibody, to examine is to investigate the mechanisms underlying menopause-induced whether FSH mediates muscle degeneration. Additionally, we skeletal muscle loss and explore therapeutic strategies to improve are investigating whether neuromuscular electrical stimulation muscle health in post-menopausal women. (NMES)canreversemenopause-relateddeclinesinmusclequality. Skeletal muscle mass and strength are critical for healthy aging, Our goal is to uncover novel mechanisms driving skeletal muscle with many referring to muscle as the ”currency of aging.” While loss post-menopause and to inform the development of targeted the post-menopausal decline in estrogen is known to contribute to muscle degeneration, the resulting loss of negative feedback on theinterventions aimed at enhancing muscle health in aging women. Build Learning through Inquiry in the Social Sciences
Abstract:
Acute myeloid leukemia (AML) is an aggressive cancer with a (SAR) studies by derivatizing the compounds using multi-step poor prognosis. Since nearly half of AML patients have mutations synthesis. We introduced both conservative and more dramatic in DNA methylation-related genes, DNA hypomethylating agents modificationstomultiplemodifiableregions,adjustingthesizeand (HMAs) are commonly used as treatment. However, HMAs alone polarityofitssidegroupswhilepreservingthecorescaffold. These show limited success, driving interest in combination therapies changes allow us to better understand which chemical features are to improve outcomes. To identify the genetic drivers of HMA criticalforactivityandhelpguidethedevelopmentofamorepotent sensitivity, our collaborator, Dr. Kim Stegmaier, conducted analog. To evaluate inhibition of USP48 by the new compounds, a CRISPR-Cas9 screen and found that the knockout of the we use a high-throughput, fluorescence-based biochemical assay deubiquitinating enzyme USP48 sensitized AML cells to HMAs. that employs ubiquitin-rhodamine as substrate, which enables As deubiquitinases (DUBs) remove ubiquitin tags from target quantitative measurement of inhibitor potency. Results from proteins and thus regulate protein stability, they are compelling these assays direct the structural design of additional analogs to therapeutic targets due to their essential cellular roles. These enhance the inhibitor. Once optimized, we intend to perform findings prompted us to develop a novel small molecule inhibitor site-directed mutagenesis to identify critical binding residues and of USP48. To pursue this, the Buhrlage lab screened over 75,000 further characterize the interaction, and investigate the effects of small molecule compounds and identified promising scaffolds pharmacological inhibition of USP48 in combination with HMAs with selectivity for USP48. Building on one of these initial in preclinical models. Ultimately, we hope this new combination hit compounds, I performed initial structure-activity-relationship will improve outcomes for patients with AML. TheRoleofFollicle-StimulatingHormone(FSH)inSkeletalMuscleLossPost- Menopause Jerome Jarjoura, Tyler McNeill, Fabrisia Ambrosio University of Tennessee Knoxville | Human Developmental and Regenerative Biology | 2026 Menopause, typically occurring around age 50, marks the end of a hypothalamic-pituitaryaxisalsoleadstoelevatedlevelsoffollicle- woman’s reproductive years and is associated with an increased stimulating hormone (FSH). The role of FSH in skeletal muscle risk of various chronic diseases. Despite these sex-specific decline, however, remains poorly understood. changes, aging research has historically relied on male preclinical models, and existing female models fail to replicate the complex Toaddressthisgap, wecompareskeletalmuscleinovariectomized hormonal landscape of human menopause. The goal of our work (OVX) female mice – a model of menopause – with that of OVX mice treated with an FSH-inhibiting antibody, to examine is to investigate the mechanisms underlying menopause-induced whether FSH mediates muscle degeneration. Additionally, we skeletal muscle loss and explore therapeutic strategies to improve are investigating whether neuromuscular electrical stimulation muscle health in post-menopausal women. (NMES)canreversemenopause-relateddeclinesinmusclequality. Skeletal muscle mass and strength are critical for healthy aging, Our goal is to uncover novel mechanisms driving skeletal muscle with many referring to muscle as the ”currency of aging.” While loss post-menopause and to inform the development of targeted the post-menopausal decline in estrogen is known to contribute to muscle degeneration, the resulting loss of negative feedback on theinterventions aimed at enhancing muscle health in aging women. Build Learning through Inquiry in the Social Sciences
Source:
Harvard / 8 Harvard-Amgen Scholars Program / 2025
Topics:
muscle, usp48, fsh, menopause, inhibitor, aml, compound, hmas, model, skeletal, aging, small
