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Articles 1 - 8 of 8
Full-Text Articles in Other Chemicals and Drugs
Design And Investigation Of Small Molecule Drugs For Potential Treatment Of Cns Disorders, Flaviviral Infections, And Cancers, Viktoriya Mashinson
Design And Investigation Of Small Molecule Drugs For Potential Treatment Of Cns Disorders, Flaviviral Infections, And Cancers, Viktoriya Mashinson
Theses & Dissertations
Chapter 1 discusses the development of antagonists against the dopamine 4 receptor (D4R) that is expressed in the motor, associative, and limbic subdivisions of the basal ganglia network and is involved in Parkinson’s disease (PD). Levodopa is the firstline drug for the management of PD symptoms but its long-term use often leads to development of levodopa-induced dyskinesia (LID). D4R antagonists have been shown to decrease the abnormal involuntary movement scores in mouse models of LID. Chapter 1 outlines the development and optimization of selective D4R antagonists for potential treatment of LID. During the investigation of our D4R antagonists we discovered …
Therapeutic Effects Of Bet Protein Inhibition In B-Cell Malignancies And Beyond, Audrey L. Smith
Therapeutic Effects Of Bet Protein Inhibition In B-Cell Malignancies And Beyond, Audrey L. Smith
Theses & Dissertations
Chronic lymphocytic leukemia (CLL) develops through a combination of intrinsic genetic defects, constitutively active survival/proliferation signaling pathways, and complex microenvironment interactions. Redundant tumor microenvironment (TME) immuno-suppressive mechanisms and epigenetic maintenance of terminal T-cell dysfunction also greatly hinder anti-tumor T-cell responses in CLL. Small-molecule agents targeting the B-cell receptor (BCR) pathway and anti-apoptotic proteins alone or in combination with chemo-immunotherapy have revolutionized the management of CLL, yet there is still a significant need for novel therapeutic strategies to yield durable tumor elimination. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetyl-lysine residues on histones to regulate gene …
Novel Spirocyclic Dimer (Spid3) Displays Potent Preclinical Effects In Hematological Malignancies, Alexandria Eiken
Novel Spirocyclic Dimer (Spid3) Displays Potent Preclinical Effects In Hematological Malignancies, Alexandria Eiken
Theses & Dissertations
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by the accumulation of mature CD5+ B-cells in the peripheral blood, bone marrow, and secondary lymphoid tissues (e.g., spleen and lymph nodes).Despite the efficacy of front-line therapies, CLL is still an incurable disease, highlighting the need for development of novel therapeutics and further study of resistance mechanisms. Within the lymph node CLL tumor microenvironment (TME), there is an upregulation of gene signatures associated with B-cell receptor (BCR) and downstream nuclear factor kappa B (NF-κB) signaling compared to CLL cells found within the blood or bone marrow niches. Additionally, BCR signaling …
Structural And Biochemical Studies Of Three Enzymes Involved In Amino Acid Metabolism To Develop Novel Drugs, Yahani Pankaja Jayasinghe Arachchige
Structural And Biochemical Studies Of Three Enzymes Involved In Amino Acid Metabolism To Develop Novel Drugs, Yahani Pankaja Jayasinghe Arachchige
Theses & Dissertations
Intrinsic drug resistance in bacteria predates the clinical use of antibiotics. Additionally, heterogeneous metabolic states and the ability of many bacteria to form biofilms further enhances bacterial survival during infection and exacerbates treatment challenges. This necessitates the identification of novel drugs against new drug targets. These studies focus on the development of compounds targeting enzymes in Mycobacterium tuberculosis (Mtb) and Staphylococcus aureus that avoid intrinsic antibiotic defenses. The Mtb-encoded homoserine transacetylase enzyme (HTA) catalyzes the first step of the methionine biosynthesis pathway that produces methionine and S-adenosyl methionine. These compounds are shown to be essential for both dormant …
Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu
Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu
Theses & Dissertations
Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell …
Design And Synthesis Of Small Molecular Probes For Cns And Kidney Disorders, Swagat H. Sharma
Design And Synthesis Of Small Molecular Probes For Cns And Kidney Disorders, Swagat H. Sharma
Theses & Dissertations
The G protein regulated inwardly rectifying potassium channels (GIRK) are a family of inwardly rectifying potassium channels and are key effectors in signaling pathways. GIRK 1/2 channel subunit, predominantly found in the brain, is involved pathophysiology of various neurological disorders including, but not limited to, epilepsy, anxiety, Parkinson's, pain, reward, and addiction. Previously, our laboratory had identified a series of urea containing molecules as GIRK1/2 preferring activators. Unfortunately, the urea series suffers from significant PK liabilities (solubility, brain penetration and high clearance). The chapter 1 of the dissertation describes our efforts in developing three new series of activators with improved …
Characterization Of Di-Aryl Urea Compounds Against Acute And Chronic Toxoplasma Gondii, Austin Sanford
Characterization Of Di-Aryl Urea Compounds Against Acute And Chronic Toxoplasma Gondii, Austin Sanford
Theses & Dissertations
Toxoplasma gondii is an obligate intracellular parasite that has infected nearly 60 million individuals in the United States alone. Acute infection causes ill effects to the fetus in utero when mothers are primarily infected, and to immunocompromised individuals. Chronic infection consists of quiescent tissue cysts located primarily in brain tissue and is capable of reverting back to the acute stage causing severe toxoplasma encephalitis in immunocompromised individuals. Current treatments for acute infection are lacking while there are no approved treatments for the clearance of chronic infection. The aim of this research was to evaluate a family of di-aryl urea compounds …
Novel Therapeutic Approaches For Juvenile Neuronal Ceroid Lipofuscinosis (Cln3), Megan Elizabeth Bosch
Novel Therapeutic Approaches For Juvenile Neuronal Ceroid Lipofuscinosis (Cln3), Megan Elizabeth Bosch
Theses & Dissertations
Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in CLN3. Neuronal loss is thought to occur via glutamate excitotoxicity; however, little is known about neuron-astrocyte glutamate regulation in JNCL. We discovered that Cln3Δex7/8 astrocytes have significantly lower basal spontaneous Ca2+ oscillations and decreased responses to glutamate, indicating a disrupted signaling network. Cln3Δex7/8 astrocytes also displayed significantly lower basal mitochondrial respiration and ATP production, suggesting impaired metabolic functions. Concurrent with diminished astrocyte metabolism and Ca2+ signaling, Cln3Δex7/8 neurons were hyper-responsive to glutamate stimulation. These studies suggest that CLN3 …