A5052372180- Acute Myeloid Leukemia Research
- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Multicomponent Synthesis of Heterocycles
- Asymmetric Synthesis and Catalysis
- Neuroblastoma Research and Treatments
- Histone Deacetylase Inhibitors Research
- Click Chemistry and Applications
- Synthesis and Reactions of Organic Compounds
- Chronic Myeloid Leukemia Treatments
- Synthesis and biological activity
- Protein Kinase Regulation and GTPase Signaling
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Synthesis and Characterization of Heterocyclic Compounds
- Retinal Development and Disorders
- Neurofibromatosis and Schwannoma Cases
- Photoreceptor and optogenetics research
- Synthesis and Biological Evaluation
- Mass Spectrometry Techniques and Applications
- DNA Repair Mechanisms
- Glioma Diagnosis and Treatment
- Peptidase Inhibition and Analysis
Cincinnati Children's Hospital Medical Center
2014-2024
University of Cincinnati
2012-2024
University of Cincinnati Medical Center
2009-2024
Case Western Reserve University
2014
Dr. Reddy's Laboratories (India)
2014
University of Tennessee Health Science Center
2009-2013
Queens College, CUNY
2013
University of Memphis
2013
City Of Hope National Medical Center
2012
City of Hope
2012
The G-protein–mediated Rho guanine nucleotide exchange factor (GEF)–Rho GTPase signaling axis has been implicated in human pathophysiology and is a potential therapeutic target. By virtual screening of chemicals that fit into surface groove the DH-PH domain LARG, G-protein–regulated GEF involved RhoA activation, subsequent validations biochemical assays, we have identified class chemical inhibitors represented by Y16 are active specifically inhibiting LARG binding to RhoA. binds junction...
Proliferating cell nuclear antigen (PCNA), a potential anticancer target, forms homotrimer and is required for DNA replication numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity affect tumor proliferation. An in silico screen compound library against crystal structure subsequent structural similarity search the ZINC chemical database were carried out derive relevant docking partners. Nine compounds, termed inhibitors...
Midkine (MDK) is a heparin-binding growth factor that highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, turn enhancing survival of tumors. Therefore, inhibition considered potential strategy for cancer therapy. In present study, we demonstrate novel small molecule compound (iMDK) targets MDK. iMDK inhibited cell MDK-positive H441 adenocarcinoma cells harbor an oncogenic KRAS mutation H520 squamous cells,...
Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through series data analysis and drug screening, we identified two compounds (i.e., NSC-311068 NSC-370284) that selectively suppress TET1 transcription 5-hydroxymethylcytosine (5hmC) modification, effectively inhibit cell viability AML with high expression TET1-high AML), including carrying t(11q23)/MLL-rearrangements...
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently untreatable. Using cell-based high-throughput screen (HTS) identify small molecules stabilize P23H-opsin mutant, which causes most cases adRP, we identified novel pharmacological chaperone opsin, YC-001. As non-retinoid molecule, YC-001 demonstrates...
HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the nonstructural protein NS4B. Extensive SAR were performed around and amide function C-3/C-6 cis stereochemistry of core essential for activity. A 10-fold increase in GT-1 potency was observed when chiral phenylcyclopropyl side chain replaced with p-fluorophenylisoxazole-carbonyl moiety (67)....
Dysregulation of innate immune signaling pathways is implicated in various hematologic malignancies. However, these have not been systematically examined acute myeloid leukemia (AML). We report that AML hematopoietic stem and progenitor cells (HSPCs) exhibit a high frequency dysregulated immune-related inflammatory pathways, referred to as oncogenic states. Through gene expression analyses functional studies human cell lines patient-derived samples, we found the ubiquitin-conjugating enzyme...
Most currently available small molecule inhibitors of DNA replication lack enzymatic specificity, resulting in deleterious side effects during use cancer chemotherapy and limited experimental usefulness as mechanistic tools to study replication. Towards development targeted inhibitors, we have focused on Mcm2-7 (minichromosome maintenance protein 2–7), a highly conserved helicase key regulatory component eukaryotic Unexpectedly found that the fluoroquinolone antibiotic ciprofloxacin...
Abstract Background Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced dysregulation makes vulnerable to targeting. Methods performed screen of compounds targeting enzymes identify potential inhibitors for the growth patient-derived cells....
Autotaxin (ATX), a lysophospholipase D, plays an important role in cancer invasion, metastasis, tumor progression, tumorigenesis, neuropathic pain, fibrotic diseases, cholestatic pruritus, lymphocyte homing, and thrombotic diseases by producing the lipid mediator lysophosphatidic acid (LPA). A high-throughput screen of ATX inhibition using lysophosphatidylcholine-like substrate fluorogenic 3 (FS-3) ∼10,000 compounds from University Cincinnati Drug Discovery Center identified several...
The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, are intimately involved in cancer pathogenesis. Activation of these is catalyzed by a special class enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed molecule screening platform for identifying lead hits targeting GEF enzyme, SOS1. We employed an ensemble structure-based virtual approach combination with tier high throughput...
We present an in silico approach for drug discovery, dubbed connectivity enhanced structure activity relationship (ceSAR). Building on the landmark LINCS library of transcriptional signatures drug-like molecules and gene knockdowns, ceSAR combines cheminformatic techniques with signature concordance analysis to connect small their targets further assess biophysical compatibility using molecular docking. Candidate compounds are first ranked a target structure-independent manner, chemical...
Abstract Mass spectrometry (MS)‐based high‐throughput screening (HTS) has tremendous potential as an alternative to current methods due its speed, sensitivity, reproducibility and label‐free readout. We recently reported that a new generation matrix‐assisted laser desorption/ionization triple quadrupole (MALDI‐QqQ) mass spectrometer is ideally suited for variety of enzyme assays protocols. However, all the targets measured date had peptide substrates were easily monitored by selected ion...
Modulation of autotaxin (ATX), the lysophospholipase D enzyme that produces lysophosphatidic acid, with small-molecule inhibitors is a promising strategy for blocking ATX-lysophosphatidic acid signaling axis. Although discovery campaigns have been successful in identifying ATX inhibitors, many reported target catalytic cleft ATX. A recent study provided evidence an additional inhibitory surface hydrophobic binding pocket ATX, confirming prior studies relied on kinetics and differential...
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to stabilize trimer structure, reduce chromatin-associated selectively inhibit tumor growth. Of these compounds, PCNA-I1 was most potent. The purpose this study is further establish targeting by...