A5049183478- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Cancer-related gene regulation
- X-ray Diffraction in Crystallography
- Genetics and Neurodevelopmental Disorders
- Crystallization and Solubility Studies
- Neuroscience and Neuropharmacology Research
- Genomics and Rare Diseases
- Wnt/β-catenin signaling in development and cancer
- Signaling Pathways in Disease
- Epigenetics and DNA Methylation
- Autism Spectrum Disorder Research
- Acute Lymphoblastic Leukemia research
- Pharmaceutical studies and practices
- Transgenic Plants and Applications
- Genomics and Phylogenetic Studies
- Adenosine and Purinergic Signaling
- DNA Repair Mechanisms
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- HIV Research and Treatment
- Nicotinic Acetylcholine Receptors Study
- Genomics and Chromatin Dynamics
- Nuclear Receptors and Signaling
Harvard University
2009-2025
Broad Institute
2016-2025
Massachusetts Institute of Technology
2009-2023
Kempten University of Applied Sciences
2023
University of Oxford
2018-2019
Stanley Center for Psychiatric Research
2012-2017
University of Montana
2017
University of Colorado Denver
2017
Fox Chase Cancer Center
2017
Athinoula A. Martinos Center for Biomedical Imaging
2017
Candida albicans is an opportunistic fungal pathogen capable of life-threatening disseminated infections particularly in immunocompromised patients. Resistance to many clinically used antifungal agents has created a need identify and develop new generation compounds for therapeutic use. A compound screen potential natural products was undertaken, identifying 12 saponins, some which have not been previously described. In the Caenorhabditis elegans model, saponins conferred nematode survival...
Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, primary--albeit often ineffective--treatment method, has remained largely unchanged over past 50 years, highlighting need for novel target discovery improved mechanism-based treatments. Here, we examined in wild type mice impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based...
Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency selectivity despite the absence of a surface-binding motif. The binding these highly efficient ligands HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high potent inhibition can be achieved through careful choice linker element only.
Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac through mechanisms that remain poorly understood. We report class I HDACs function as signal-dependent repressors via inhibition the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, nuclear negatively regulates prohypertrophic signaling by ERK1/2. Inhibition DUSP5 requires activity ERK kinase,...
Significance Recent large-scale sequencing efforts have enabled the detection of millions missense variants. Elucidating their functional effect is crucial importance but challenging. We approach this problem by performing a wide-scale characterization variants from 1,330 disease-associated genes using >14,000 protein structures. identify 3D features associated with pathogenic and benign that unveiled mutations’ at molecular level. further extend our analysis to account for different...
Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting context of cardiovascular central nervous system dysfunction. Development a molecular agent for non-invasive imaging elucidate distribution functional roles HDACs humans will accelerate medical research drug discovery this domain. Herein,...
Candida albicans, the most common human pathogenic fungus, can establish a persistent lethal infection in intestine of microscopic nematode Caenorhabditis elegans. The C. elegans–C. albicans model was previously adapted to screen for antifungal compounds. Modifications this have been made facilitate high-throughput assay including co-inoculation nematodes with and instrumentation allowing precise dispensing worms into wells, eliminating two labor-intensive steps. This method utilized library...
Aiming towards the development of novel nootropic therapeutics to address cognitive impairment common a range brain disorders, we set out develop highly selective small molecule inhibitors HDAC2, chromatin modifying histone deacetylase implicated in memory formation and synaptic plasticity. Novel ortho-aminoanilide were designed evaluated for their ability selectively inhibit HDAC2 versus other Class I HDACs. Kinetic thermodynamic binding properties essential elements our design strategy two...
We disclose the first small molecule histone deacetylase (HDAC) inhibitor (3, BRD73954) capable of potently and selectively inhibiting both HDAC6 HDAC8 despite fact that these isoforms belong to distinct phylogenetic classes within HDAC family enzymes. Our data demonstrate meta substituents phenyl hydroxamic acids are readily accommodated upon binding and, furthermore, necessary for potent inhibition HDAC8.
Paralog-selective inhibitors of GSK3 kinases were designed by exploiting a single amino acid difference in their ATP-binding domains and studied AML.
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity represent disease-modifying targets for several disorders, including Alzheimer's disease major depressive disorder. Because poor pharmacokinetic properties BDNF, the interest in small-molecule TrkB agonists modulators is high. Several compounds been reported to act agonists, their increasing use various nervous system disorder models creates...
Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it difficult to dissect the role individual HDACs due lack selective small-molecule inhibitors. Here, we report synthesis series highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes clinically experienced inhibitor CI-994. We used this toolkit isochemogenic or chemically matched...
Abstract Glycogen synthase kinase‐3 (GSK‐3) regulates multiple cellular processes in diabetes, oncology, and neurology. N ‐(3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(3‐chloro‐4‐methoxyphenyl)oxazole‐4‐carboxamide (PF‐04802367 or PF‐367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK‐3 to date. Its efficacy was demonstrated modulation tau phosphorylation vitro vivo. Whereas kinetics PF‐367 binding brain tissues are too fast for an effective...
Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized combination of small molecule and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) be targeted selective induction latent HIV-1 expression. Individual depletion HDAC3 significantly induced expression from promoter in 2D10 latency cell line model. However, HDAC1 or −2 alone did...