Jennifer Bardenhagen
A5089004171- Cancer, Hypoxia, and Metabolism
- Biochemical and Molecular Research
- Amino Acid Enzymes and Metabolism
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Glioma Diagnosis and Treatment
- DNA Repair Mechanisms
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- ATP Synthase and ATPases Research
- Cancer Genomics and Diagnostics
- Genetic Neurodegenerative Diseases
- Cancer-related Molecular Pathways
- Histone Deacetylase Inhibitors Research
- Drug Transport and Resistance Mechanisms
- Acute Myeloid Leukemia Research
- Metabolomics and Mass Spectrometry Studies
- Diabetes Treatment and Management
- Epigenetics and DNA Methylation
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related gene regulation
- Cytokine Signaling Pathways and Interactions
- RNA Research and Splicing
- Cancer therapeutics and mechanisms
The University of Texas MD Anderson Cancer Center
2014-2024
Institute for Applied Science
2022
Lexicon Pharmaceuticals (United States)
2019
The University of Texas Health Science Center at Houston
2015
The bromodomain containing proteins TRIM24 (tripartite motif protein 24) and BRPF1 (bromodomain PHD finger 1) are involved in the epigenetic regulation of gene expression have been implicated human cancer. Overexpression correlates with poor patient prognosis, is a scaffolding required for assembly histone acetyltransferase complexes, where MOZ (monocytic leukemia zinc protein) was first identified as recurrent fusion partner patients (8p11 chromosomal rearrangements). Here, we present...
The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies highly effective at reducing vertebral but not fractures. Cortical bone is a major determinant of strength. To identify novel drug targets, we phenotyped cortical 3 366 viable mouse strains with global knockouts druggable genes. thickness was substantially elevated in Notum-/- mice. NOTUM secreted WNT lipase observed high expression osteoblasts osteoclasts. Three...
Inhibition of glutaminase-1 (GLS-1) hampers the proliferation tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused optimizing pharmacokinetic properties, developed new selective inhibitor, compound 27 (IPN60090), which is currently phase 1 clinical trials. Compound attains high oral preclinical species, with...
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ RNAi-based in vivo functional genomics platform determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, identify protein arginine methyltransferase 1 (PRMT1) as critical dependency required for maintenance. Genetic and pharmacological studies validate the role PRMT1 maintaining growth. Mechanistically, using proteomic...
The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports inhibitors directed toward sodium-dependent glucose cotransporter 2 (SGLT2) as method maintaining homeostasis in diabetic patients. Herein we report discovery novel O-xyloside 7c that inhibits SGLT2 vitro urinary reabsorption vivo.
Proteins that 'read' the histone code are central elements in epigenetic control and bromodomains, which bind acetyl-lysine motifs, increasingly recognized as potential mediators of disease states. Notably, first BET bromodomain-based therapies have entered clinical trials there is a broad interest dissecting therapeutic relevance other bromodomain-containing proteins human disease. Typically, drug development facilitated expedited by high-throughput screening, where assays need to be...
Mutations in the ATM gene are common multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement loss function (LOF) as a predictive biomarker response is urgently needed.
Preventing histone recognition by bromodomains emerges as an attractive therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA domain-containing 2 isoform A) cancer cells is associated with poor prognosis making the bromodomain a promising epigenetic target. In development vitro assay and identification small molecule ligands, we conducted structure-guided studies which revealed conformationally flexible bromodomain. Structural on apo-, peptide-and molecule-ATAD2...
One of the hallmarks cancer is high levels DNA replication stress and defects in damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia Rad3-related protein (ATR) a key regulator DDR machinery an attractive therapeutic target, with multiple ATR inhibitors holding significant promise ongoing clinical studies. Herein, we describe discovery characterization ART0380 (6), potent selective inhibitor compelling vitro vivo pharmacological profile...
Abstract Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy macromolecule building blocks for rapid growth. Metabolic vulnerabilities caused by inactivation of render tumor highly dependent OXPHOS, represent a therapeutic opportunity. Through an extensive medicinal chemistry campaign, we have identified IACS-10759 as potent inhibitor complex I OXPHOS. effectively inhibits ATP production oxygen consumption in isolated mitochondria,...
Abstract Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy macromolecule building blocks needed enable continued tumor cell growth. Genetic or epigenetic inactivation of one these two redundant pathways represents a metabolic vulnerability that should be susceptible an inhibitor other pathway. Through extensive medicinal chemistry campaign, IACS-10759 was identified as potent complex I phosphorylation. In isolated mitochondria...
<div>AbstractPurpose:<p>Mutations in the <i>ATM</i> gene are common multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement ATM loss function (LOF) as a predictive biomarker response is urgently needed.</p>Experimental Design:<p>We present first disclosure and preclinical development novel, selective ATR inhibitor, ART0380, test its antitumor activity cancer models. To refine LOF biomarker,...
<div>AbstractPurpose:<p>Mutations in the <i>ATM</i> gene are common multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement ATM loss function (LOF) as a predictive biomarker response is urgently needed.</p>Experimental Design:<p>We present first disclosure and preclinical development novel, selective ATR inhibitor, ART0380, test its antitumor activity cancer models. To refine LOF biomarker,...
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Abstract Acute myeloid leukemia (AML) is a highly aggressive disease with high mortality rate that encompasses several genetically and clinically diverse hematological malignancies characterized by clonal expansion of transformed stem/progenitor cells limited ability to differentiate into mature blood cells. Standard care for AML has progressed minimally in the past 30 years relapse/refractory AML, survival rates &lt;12% those aged &gt;65 years. Therefore, novel, effective...
Abstract Tumor cells depend on both glycolysis and oxidative phosphorylation (OXPHOS) for energy biomass production leading to robust cell proliferation. Recent data has demonstrated a dependence of various tumor types mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through extensive medicinal chemistry campaign, IACS-10759 was identified as potent, selective inhibitor complex I the electron transport chain, is orally bioavailable excellent PK physicochemical...
Abstract Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy macromolecule building blocks needed enable continued tumor cell growth. Genetic or epigenetic inactivation of one these two redundant pathways represents a metabolic vulnerability that should be susceptible an inhibitor other pathway. We have identified multiple contexts where all subset tumors demonstrate dependence mitochondrial OXPHOS, which exciting therapeutic...
Abstract Inhibition of mitochondria complex I in tumors that are metabolically dependent on oxidative phosphorylation (OXPHOS) for their survival offers unique synthetic lethal opportunities. Examples contexts AML and DLBCL, where OXPHOS is highly active subpopulations glioblastoma neuroblastoma possess genetic alterations which make them glycolysis deficient. In addition, several lines evidence indicate after treatment with chemo or targeted therapy, residual tumor cells become reliant...
Abstract Acute myeloid leukemia (AML) is a highly aggressive disease that made up of several genetically and clinically diverse hematological malignancies are characterized by clonal expansion malignant stem/progenitor cells with limited ability to differentiate into mature blood cells. Standard care for AML has progressed minimally in the past 30 years relapse/refractory AML, survival rates &lt;12% those aged &gt;65 years. Therefore, novel, effective therapeutics needed this...
Abstract MTH1 is a protein that sanitizes oxidized dNTPs in the cell. It preferentially hydrolyzes 8-oxo-dGTP and 2-OH-dATP to their corresponding monophosphates thereby prevents incorporation of nucleotides into DNA or RNA. The functional result reduction down-stream mutations, damage, thus preventing cell death. Recent publications suggest non-essential enzyme normal cells, but required for survival cancer cells as consequence being subjected high levels oxidative stress; hence its...