A5037496059- Synthesis and Reactivity of Heterocycles
- Biochemical and Molecular Research
- Synthesis and Characterization of Heterocyclic Compounds
- Cancer-related Molecular Pathways
- HIV/AIDS drug development and treatment
- Receptor Mechanisms and Signaling
- Synthesis and biological activity
- DNA and Nucleic Acid Chemistry
- Synthesis and Reactions of Organic Compounds
- Endoplasmic Reticulum Stress and Disease
- Nicotinic Acetylcholine Receptors Study
- Urban Stormwater Management Solutions
- Enzyme Structure and Function
- Ubiquitin and proteasome pathways
- Chemical Synthesis and Analysis
- Estrogen and related hormone effects
- Vitamin D Research Studies
- Neuroscience and Neuropharmacology Research
- Microtubule and mitosis dynamics
- Crystal structures of chemical compounds
- Amino Acid Enzymes and Metabolism
- Acute Lymphoblastic Leukemia research
- Neuropeptides and Animal Physiology
- Ion channel regulation and function
- Polyamine Metabolism and Applications
Janssen (United States)
2020-2025
Springhouse
2020-2023
Janssen (Belgium)
2022-2023
Amgen (United States)
2012-2022
MSM Protein Technologies (United States)
2022
Construction Industry Research and Information Association
2012-2013
Oregon Health & Science University
2009
Vollum Institute
2009
Duke University
2004-2005
Duke University Hospital
2002-2005
Steroid receptors bind as dimers to a degenerate set of response elements containing inverted repeats hexameric half-site separated by 3 bp spacer (IR3). Naturally occurring selective androgen have recently been identified that resemble direct the (ADR3). The 3D crystal structure receptor (AR) DNA-binding domain bound ADR3 reveals an unexpected head-to-head arrangement two protomers rather than expected head-to-tail seen in nuclear similar geometry. Compared with glucocorticoid receptor,...
Amino acid, polyamine, and organocation (APC) transporters are secondary that play essential roles in nutrient uptake, neurotransmitter recycling, ionic homeostasis, regulation of cell volume. Here, we present the crystal structure apo-ApcT, a proton-coupled broad-specificity amino acid transporter, at 2.35 angstrom resolution. The contains 12 transmembrane helices, with first 10 consisting an inverted structural repeat 5 helices like leucine transporter LeuT. ApcT reveals inward-facing, apo...
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor MDM2-p53 interaction. Continued research investigation N-alkyl substituent this series, focused in particular on previously underutilized interaction shallow cleft MDM2 surface, led to one-carbon tethered sulfone which gave rise substantial improvements biochemical cellular potency. Further produced AMG 232 (2), is currently being evaluated human clinical trials for treatment cancer. Compound 2...
N-Methyl-d-aspartate receptors are ionotropic glutamate that mediate fast excitatory neurotransmission in the central nervous system. These play essential roles synaptic plasticity, learning, and memory implicated various neuropathological psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 MPX-007 potent selective for GluN2A receptors, yet their physical properties limit vivo utility. In this study, we...
Water-sensitive urban design (WSUD) is a concept that gaining support as means to manage water systems in an integrated way through the better positioning of topic planning and processes. emerging UK this paper sets scene identifies opportunities constraints from perspective. Recent developments management, ecosystem services multifunctional land use provide new for ‘getting more less’. These can range seeing all forms resource, exploiting contribute green blue infrastructure agendas,...
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor MDM2–p53 interaction. Our continued search for diverse analogues led to novel morpholinone MDM2 inhibitors. This change core has significant impact on both potency metabolic stability compared series. Within this series, AM-8735 emerged as an with remarkable biochemical (HTRF IC50 = 0.4 nM) cellular (SJSA-1 EdU 25 nM), well pharmacokinetic properties. Compound 4 also shows excellent...
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led design synthesis tetrasubstituted morpholinone 10, an inhibitor with a biochemical IC50 1.0 μM. The cocrystal structure 10 inspired two independent optimization strategies resulted in discovery morpholinones 16 27 possessing distinct binding modes. Both analogues were potent inhibitors cellular assays, (IC50 = 0.10 μM) also displayed suitable PK profile for vivo animal...
The structure-based design and optimization of a novel series selective PERK inhibitors are described resulting in the identification 44 as potent, highly selective, orally active tool compound suitable for pathway biology exploration both vitro vivo.
GRP94 is the endoplasmic reticulum paralog of cytoplasmic Hsp90. Models Hsp90 action posit an ATP-dependent conformational switch in N-terminal ligand regulatory domain chaperone. However, crystal structures isolated N-domain complex with a variety ligands have yet to demonstrate such change. We determined structure ATP, ADP, and AMP. Compared N-ethylcarboxamidoadenosine radicicol-bound forms, these reveal large rearrangement protein. The nucleotide-bound form exposes new surfaces that...
We previously reported the discovery of potent and selective morpholinone piperidinone inhibitors MDM2-p53 interaction. These have in common a carboxylic acid moiety that engages an electrostatic interaction with MDM2-His96. Our continued search for diverse led to novel replacements these acids uncovering new interactions MDM2 protein. In particular, using pyridine or thiazole as isosteres resulted very analogues. From these, AM-6761 (4) emerged inhibitor remarkable biochemical (HTRF IC50 =...
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor MDM2-p53 association, which is currently being evaluated in human clinical trials for treatment cancer. Further modifications 1, including replacing carboxylic acid with 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic...
Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission painful stimuli. Herein, we describe identification hit-to-lead optimization a novel class tricyclic sulfonamides allosteric GlyR potentiators. Initial high-throughput screening (HTS) hit 1 led 3, which...
The salt-inducible kinases (SIK) 1–3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. lack highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study optimal isoform selectivity profile suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy developing potent that selective against other by engaging two differentiating features catalytic...
Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by inability myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) an enzyme well-known in pyrimidine biosynthesis pathway preclinical findings demonstrated that DHODH metabolic vulnerability AML as inhibitors can induce differentiation across multiple subtypes. As result virtual screening structure-based drug design approaches, novel series...
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While half-life extended monoclonal antibody 2 vaccines have recently been approved for infants respectively, options to prevent disease patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, long-acting PK when injected an aqueous suspension, suggesting...
The vitamin D receptor (VDR) is a ligand-responsive transcription factor that forms active, heterodimeric complexes with the 9-cis retinoic acid (RXR) on response elements (VDREs). Both proteins consist of an N-terminal DNA-binding domain, C-terminal ligand-binding and intervening hinge region. length requirements for both transcriptional regulation DNA binding have not been studied to date any member steroid hormone superfamily. We generated series internal deletion mutants VDR found as few...
Continued optimization of the N-substituent in piperidinone series provided potent piperidinone–pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties rats. Reducing structure complexity N-alkyl substituent led to discovery 23, a simplified inhibitor MDM2. Compound 23 exhibits excellent substantial vivo antitumor activity SJSA-1 osteosarcoma xenograft mouse model.
Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared current anticoagulants. The discovery of potent FXIa good oral bioavailability has been challenging. Herein, we describe our effort, utilizing nonclassical interactions to improve potency, cellular permeability, and by enhancing the binding while reducing polar atoms. Beginning literature-inspired pyridine N-oxide-based inhibitor 1, imidazole linker was first replaced a pyrazole moiety...