A5059546399- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Receptor Mechanisms and Signaling
- Chemokine receptors and signaling
- Protein Kinase Regulation and GTPase Signaling
- T-cell and B-cell Immunology
- Cellular transport and secretion
- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Asthma and respiratory diseases
- Melanoma and MAPK Pathways
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
- interferon and immune responses
- Cancer Research and Treatments
- Microtubule and mitosis dynamics
- Photosynthetic Processes and Mechanisms
- Immune cells in cancer
- Antimicrobial Peptides and Activities
- Retinal Imaging and Analysis
- Adenosine and Purinergic Signaling
- Protein Tyrosine Phosphatases
University of Illinois Chicago
2014-2025
University of Illinois Hospital & Health Sciences System
2024
St. Jude Children's Research Hospital
2023
University of Illinois Urbana-Champaign
2013-2020
Ashland (United States)
2017
Illinois College
2013-2014
Acute lung injury (ALI) is a lethal inflammatory disorder whose incidence on the rise. Alveolar macrophages normally act to resolve inflammation, but when dysregulated they can provoke ALI. We demonstrate that monocyte-derived (CD11b+ macrophages) recruited into airspace upregulate anti-inflammatory function of alveolar by suppressing their stimulator type 1 interferon gene (STING) signaling. Depletion CD11b+ in mice (macrophagedep mice) after endotoxin or Pseudomonas aeruginosa causes...
Repeated dosing of drugs targeting G protein-coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy AMD3100, a competitive the chemokine receptor CXCR4 that mobilizes leukemic blasts from bone marrow into blood sensitize them chemotherapy, is reduced after prolonged treatment. Tolerance AMD3100 increases abundance on surface blasts, promotes rehoming marrow. inhibits both protein signaling by and...
Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of novel series C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization entropic loss upon ligand binding use unique "open" conformation site yielded successful strategy improvement both potency selectivity. The TIQ-based 3g 3n exhibited highest 82 55 nM 330- 135-fold selectivity over HDAC1,...
Aggregation of α-synuclein, the hallmark α-synucleinopathies such as Parkinson's disease, occurs in various glycosphingolipidoses. Although α-synuclein aggregation correlates with deficiencies lysosomal degradation glycosphingolipids (GSL), mechanism(s) involved this remains unclear. We previously described Krabbe's disease (KD), a neurodegenerative glycosphingolipidosis caused by deficiency galactosyl-ceramidase (GALC) and accumulation GSL psychosine. Here, we used multi-pronged approach...
RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development inhibitors, but efficacy these inhibitors remains limited by resistance. Here, we developed pan-RAS inhibitor, ADT-007, binds nucleotide-free to block GTP activation effector interactions and MAPK/AKT signaling, resulting in mitotic arrest apoptosis. ADT-007 potently inhibited growth mutant cells irrespective mutation or isozyme, RASWT with GTP-activated from upstream...
Regenerating vascular endothelium under sepsis, trauma, and viral infections is vital for promoting the resolution of inflammatory diseases such as acute lung injury (ALI). Transient receptor potential canonical (TRPC) channels mediated Ca2+ entry compromises organ functions survival from injury. Through decoding domain in TRPC6 responsible injury, we unveiled intricate molecular mechanisms underlying regeneration injured tissue. We found that substitution isoleucine111 within Ist ankyrin...
RAS is the most frequently mutated oncogene in cancer. proteins show high sequence similarities their G-domains but are significantly different C-terminal hypervariable regions (HVR). These interact with cell membrane via lipid anchors that result from posttranslational modifications (PTM) of cysteine residues. KRAS4b unique as it has only one undergoes PTM, C185. Small molecule covalent modification C185 would block any form prenylation and subsequently inhibit attachment to membrane,...
ABSTRACT Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective mutation or isozyme. WT with GTP-activated from upstream mutations were equally sensitive. Conversely, harboring downstream BRAF and normal essentially insensitive to ADT-007. Sensitivity ADT-007 required activated dependence on for proliferation, while insensitivity was attributed metabolic deactivation by UDP-glucuronosyltransferases expressed in but...
Abstract Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (−)) cancers. Epigenetic reactivation target genes using histone deacetylase (HDAC) inhibitors has been proposed ER (−) cancers to resensitize therapy selective modulators (SERMs) that are effective (+) treatment. Based upon preliminary studies breast cells treated with combinations HDAC SERMs, hybrid drugs, termed SERMostats, were designed computational...
Histone deacetylase 3 (HDAC3) is a promising epigenetic drug target for multiple therapeutic applications. Direct interaction between the Deacetylase Activating Domain of silencing mediator retinoid or thyroid-hormone receptors (SMRT-DAD) required activation enzymatic activity HDAC3. The structure this complex and nature interactions with HDAC inhibitors in solution are unknown. Using novel photoreactive probes, "nanorulers", we determined distance catalytic site full-length HDAC3 SMRT-DAD...
Abstract Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models cancer, and preliminary metabolism pharmacokinetic studies (DMPK) series secondary tertiary N‐substituted 7‐aminoheptanohydroxamic acid‐based HDAC inhibitors. Introduction an amino group with one or two surface binding groups (SBGs) yielded successful strategy to develop novel potent The amines were...
We observed in PRESTO-Tango β-arrestin recruitment assays that the α1-adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. screened a panel of 14 α1/2- and β1/2/3-AR antagonists for CXCR4 atypical (ACKR)3 agonist activity against cognate CXCL12. multiple α1-AR activate (CXCL12 = cyclazosin > doxazosin) ACKR3 alfuzosin doxazosin phentolamine terazosin silodosin tamsulosin). The two...
End-binding proteins (EBs) associate with the growing microtubule plus ends to regulate dynamics as well interaction intracellular structures. EB3 contributes pathological vascular leakage through interacting inositol 1,4,5-trisphosphate receptor 3 (IP3R3), a calcium channel located at endoplasmic reticulum membrane. The C-terminal domain of (residues 200–281) is functionally important for this because it contains effector binding sites, prerequisite activity and specificity. Structural data...