A5003698505- Cell death mechanisms and regulation
- Computational Drug Discovery Methods
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
- Protein Structure and Dynamics
- Psoriasis: Treatment and Pathogenesis
- ATP Synthase and ATPases Research
- Protein Kinase Regulation and GTPase Signaling
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Melanoma and MAPK Pathways
- Multiple Myeloma Research and Treatments
- Mass Spectrometry Techniques and Applications
- Biochemical and Molecular Research
- Synthesis and biological activity
- RNA Interference and Gene Delivery
- Mitochondrial Function and Pathology
- Cancer therapeutics and mechanisms
- Click Chemistry and Applications
- Cytokine Signaling Pathways and Interactions
- Chronic Lymphocytic Leukemia Research
- Cancer, Hypoxia, and Metabolism
AbbVie (United States)
2016-2025
Abbott Fund
2005-2011
Abbott (United Kingdom)
2011
Abbott (United States)
1999-2008
Discovery Laboratories (United States)
2007
Neurocrine Biosciences (United States)
2004
General Atomics (United States)
2004
University of Virginia
1999
Dartmouth College
1997-1998
Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated tumor growth, pathogenesis, resistance to chemo- or radiotherapy. On the basis NMR structure a SMAC peptide complexed with BIR3 domain X-linked IAP (XIAP), novel series XIAP antagonists was discovered. The most potent compounds this bind baculovirus repeat 3 (BIR3) single-digit nanomolar affinity promote cell death several human cancer lines. In MDA-MB-231 breast mouse xenograft model, these...
Abstract TRPA1 is an ion channel and has been proposed as a thermosensor across species. In invertebrate ancestral vertebrates such fly, mosquito, frog, lizard snakes, serves heat receptor, sensory input utilized for avoidance or infrared detection. However, in mammals, whether receptor noxious cold highly controversial, activation by was observed some groups but disputed others. Here we attribute the discrepancy to species differences. We show that activates rat mouse not human rhesus...
The inhibitor of apoptosis proteins (IAPs) regulate the caspase family cysteine proteases, which play an important role in execution programmed cell death. Human X-linked protein (XIAP) is a potent caspases-3, -7, and -9. Here we show that Bir3 domain minimal region XIAP needed for caspase-9 inhibition. three-dimensional structure XIAP, determined by NMR spectroscopy, resembles classical zinc finger consists five α-helices, three-stranded β-sheet, atom chelated to three cysteines one...
The apoptosome is a multiprotein complex comprising Apaf-1, cytochrome c, and caspase-9 that functions to activate caspase-3 downstream of mitochondria in response apoptotic signals. Binding c dATP Apaf-1 the cytosol leads assembly heptameric which each subunit bound noncovalently procaspase-9 via their respective CARD domains. Assembly results proteolytic cleavage at site PEPD315 yield large (p35) small (p12) subunits. In addition PEPD site, contains (DQLD330), when cleaved, produces...
Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report series MCL-1 inhibitors emanated from high throughput screening (HTS) hit progressed via iterative cycles structure-guided design. Advanced compounds this exhibited subnanomolar affinity for excellent selectivity over other proteins as well kinases GPCRs. In dependent human line, administration compound 30b rapidly induced caspase...
The development of bromodomain and extraterminal domain (BET) inhibitors their examination in clinical studies, particularly oncology settings, has garnered substantial recent interest. An effort to generate novel BET with excellent potency drug metabolism pharmacokinetics (DMPK) properties was initiated based upon elaboration a simple pyridone core. Efforts develop bidentate interaction critical asparagine residue resulted the incorporation pyrrolopyridone core, which improved by 9–19-fold....
eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits activity, attenuates global protein synthesis and upregulates set of stress-response proteins. Partial loss-of-function mutations in cause neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed small molecule ISRIB specific activator (<xref ref-type="bibr"...
The rapid spread of the recent Zika virus (ZIKV) epidemic across various countries in American continent poses a major health hazard for unborn fetuses pregnant women. To date, there is no effective medical intervention. nonstructural protein 5 (ZIKV-NS5) critical ZIKV replication through 5′-RNA capping and RNA polymerase activities present its N-terminal methyltransferase (MTase) C-terminal RNA-dependent (RdRp) domains, respectively. crystal structure full-length ZIKV-NS5 has been...
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, structural analog the potent GPX4 inhibitor RSL3, has much better plasma stability (t1/2 > 5 h mouse plasma). The bioavailability 24 provided efficacious drug concentrations with IP dosing, thus enabling vivo studies assess tolerability and efficacy. An efficacy study using GPX4-sensitive tumor...
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family enzymes. They in response to certain cytokines, as well by cellular stresses including chemotoxins, peroxides, irradiation. have been implicated pathology a variety different diseases with an inflammatory component asthma, stroke, Alzheimer's disease, type 2 diabetes mellitus. In this work, high-throughput screening identified JNK inhibitor excellent selectivity profile. Using...
The pituitary adenylate cyclase-activating polypeptide (PACAP) receptor is a class II G protein-coupled that contributes to many different cellular functions including neurotransmission, neuronal survival, and synaptic plasticity. solution structure of the potent antagonist PACAP (residues 6'-38') complexed N-terminal extracellular (EC) domain human splice variant hPAC1-R-short (hPAC1-R(S)) was determined by NMR. peptide adopts helical conformation when bound hPAC1-R(S) with bend at residue...
Ion channels play critical roles in signaling processes and are attractive targets for treating various diseases. Here we describe an NMR-based strategy structural analyses of potassium channel-ligand complexes using KcsA (residues 1-132, with six mutations to impart toxin binding mimic the eukaryotic hERG channel). Using this approach, determined solution structure complex high-affinity peptide antagonist charybdotoxin. The data reveal how charybdotoxin binds closed form makes specific...
TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine lysine residues, can be activated by electrophilic compounds, including active ingredients pungent natural products (e.g., allyl isothiocyanate), environmental irritants acrolein), endogenous ligands (4-hydroxynonenal). However, how leads to opening not understood. Here, we report that electrophilic, thioaminal-containing...
Members of the BET family bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety cancer cell lines. A two-dimensional NMR fragment screen binders to bromodomains BRD4 phenylpyridazinone with weak binding affinity (1, Ki = 160 μM). SAR investigation 1, aided by X-ray structure-based design, enabled synthesis potent pyridone and macrocyclic inhibitors exhibiting single digit nanomolar potency both biochemical based assays. Advanced...
Abstract IL-36 cytokines are pro-inflammatory members of the IL-1 family that upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed active psoriatic lesions and can drive processes 3D human skin equivalents supporting a role for this target inflammation. Small molecule antagonists interleukins have been historically challenging to generate. Nevertheless, we performed small high-throughput screen identify using novel TR-FRET binding assay. Several compounds,...
The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib irreversibly binds BTK at Cys 481 , inhibiting its activity and thus blocking transduction of B cell receptor (BCR) signaling. Although is durably effective in patients with malignancies, many still develop ibrutinib-resistant disease. Resistance can arise because mutations the ibrutinib-binding site BTK. Here, we characterized mechanism by which two mutations, C481F C481Y, may lead to resistance. Both mutants lacked detectable vitro...
Hematopoietic progenitor kinase 1 (HPK1) is an MAP4K family member within the Ste20-like serine/threonine branch of kinome. HPK1 expression limited to hematopoietic cells and has a predominant role as negative regulator T cell function. Because central/dominant in negatively regulating function, long been center interest potential pharmacological target for immune therapy. The development small molecule inhibitor remains challenging because need high specificity relative other kinases,...