A5008934311- Drug Transport and Resistance Mechanisms
- Pharmacogenetics and Drug Metabolism
- Ion channel regulation and function
- Estrogen and related hormone effects
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Computational Drug Discovery Methods
- HER2/EGFR in Cancer Research
- Drug-Induced Hepatotoxicity and Protection
- Cholinesterase and Neurodegenerative Diseases
- Cancer Mechanisms and Therapy
- Cancer therapeutics and mechanisms
- Inflammatory mediators and NSAID effects
- Pharmacological Effects and Toxicity Studies
- Adenosine and Purinergic Signaling
- Pain Mechanisms and Treatments
- Peptidase Inhibition and Analysis
- Analytical Chemistry and Chromatography
- Phytochemical compounds biological activities
- Advanced Breast Cancer Therapies
- Synthesis and Biological Evaluation
- Neuroscience and Neuropharmacology Research
- Anesthesia and Pain Management
- Cardiac, Anesthesia and Surgical Outcomes
- Protein Interaction Studies and Fluorescence Analysis
Exelixis (United States)
2022-2025
Taipei Medical University
2014-2024
Bristol-Myers Squibb (United States)
2023
Yecuris (United States)
2023
Takeda (United States)
2023
FH Aachen
2023
AbbVie (Germany)
2023
Ultragenyx Pharmaceutical (United States)
2022
Yeungnam University
2015-2020
Massachusetts General Hospital
2017
Breast cancer remains a leading cause of death in women, representing significant unmet medical need. Here, we disclose our discovery efforts culminating clinical candidate, 35 (GDC-9545 or giredestrant). is an efficient and potent selective estrogen receptor degrader (SERD) full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing preclinical...
Infection with the intestinal helminth parasite Heligmosomoides polygyrus exacerbates colitis caused by bacterial enteropathogen Citrobacter rodentium. To clarify underlying mechanism, we analyzed fecal microbiota composition of control and helminth-infected mice evaluated functional role compositional differences transplantation experiments. Our results showed that infection Balb/c H. resulted in significant changes gut microbiota, characterized a marked increase abundance Bacteroidetes...
Tumor necrosis factor alpha (TNF-α) driven processes are involved at multiple stages of Alzheimer's disease (AD) pathophysiology and progression. Biologic TNF-α inhibitors (TNFIs) the most potent class TNFIs but cannot be developed for AD since these macromolecules do not cross blood–brain barrier (BBB). A BBB-penetrating TNFI was engineered by fusion extracellular domain type II human TNF receptor (TNFR) to a chimeric monoclonal antibody (mAb) against mouse transferrin (TfR), designated as...
Strong human genetic evidence points to an essential contribution of the voltage-gated sodium channel Nav1.7 pain sensation: loss function leads congenital insensitivity pain, whereas gain-of-function mutations in SCN9A gene that encodes cause painful neuropathies, such as inherited erythromelalgia, a syndrome characterized by episodic spontaneous pain. Selective blockers thus hold promise potential painkillers with improved safety and reduced unwanted side effects compared existing...
The Food and Drug Administration recommends rosuvastatin dosage reductions in Asian patients because pharmacokinetic studies have demonstrated an approximate 2-fold increase median exposure to subjects compared with Caucasian controls. Yet, no explanation for this ethnic difference has been confirmed. Here we show that Asians Whites does not differ significantly when all are wild-type carriers both solute carrier organic anion transporter 1B1 *1a ATP-binding cassette subfamily G member 2...
We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors the human sodium channel hNaV1.7. The optimization these is described. aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models acute inflammatory pain demonstrated binding voltage sensor domain 4 site NaV1.7 leads an effect vivo. Our findings corroborate importance...
Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled development second generation selective Nav1.7 inhibitors show robust inflammatory and neuropathic at low IC50. Like earlier arylsulfonamides, these newer...
The utilization of in vitro data to predict drug pharmacokinetics (PK) vivo has been a consistent practice early discovery for decades. However, its success is hampered by mispredictions attributed uncharacterized biological phenomena/experimental artifacts. Predicted clearance (CL) from experimental (i.e., intrinsic clearance: CL<sub>int</sub>; fraction unbound plasma: f<sub>u,p</sub>) often systematically underpredicted using the well-stirred model (WSM). objective this study was evaluate...
Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body. Bilirubin elimination is a multifaceted process consisting uptake into hepatocytes facilitated by OATP1B1 and OATP1B3. Once in hepatocytes, it extensively glucuronidated UGT1A1. Eventually, glucuronide metabolite excreted bile via MRP2. UGT1A1 inhibition has been previously shown be linked with hyperbilirubinemia. However, because drug transporters also contribute elimination, purpose this work was...
Adiponectin predominantly secreted from adipose tissue has exhibited potent anti‐proliferative properties in cancer cells via modulating cell cycle and apoptosis. FoxO3A, a Forkhead box O member of the transcription factor, plays critical role expression genes involved death and/or survival. In this study, we investigated FoxO3A signaling anti‐cancer activities adiponectin. Herein, have shown that treatment with globular adiponectin (gAcrp) increases p27 but decreases cyclinD1 human hepatoma...
Pim kinases have been targets of interest for a number therapeutic areas. Evidence durable single-agent efficacy in human clinical trials validated kinase inhibition as promising approach multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), potent, orally bioavailable, and well tolerated pan-Pim inhibitor that proved efficacious RPMI8226 MM.1S xenograft mouse models has evaluated an early development candidate.
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Background: Protein kinase, membrane-associated tyrosine/threonine-1 (PKMYT1) phosphorylates cyclin-dependent kinase 1 (CDK1) at threonine-14 (Thr14), inhibiting the catalytic activity of CDK1/cyclin B complex, which blocks cells in G2 from entering M phase. Disruption this PKMYT1-mediated G2/M checkpoint cancer allows mitotic events to occur while DNA synthesis is still ongoing, resulting catastrophic levels damage and cell death. We report preclinical data for XL495, a potent selective...
Abstract Background: Ubiquitin-specific protease 1 (USP1) catalyzes selective removal of ubiquitin from its substrate proteins. During translesion synthesis (TLS), USP1 cleaves proliferating cell nuclear antigen (PCNA), facilitating exchange TLS polymerases for polymerase delta. Inhibition prevents the repair DNA lesions by TLS, resulting in single-stranded gaps which are synthetically lethal with BRCA1/2 mutations. Poly (ADP-ribose) (PARP) inhibitors have shown clinical benefit BRCA-mutated...
With the increasingly serious problem of stray animals in cities, traditional manual monitoring and management methods are unable to meet real-time efficient needs animals. Therefore, this article designs a city animal supervision testing model based on YOLOv8 Flink. This identifies determines their species video streams captured by camera. It simultaneously uses processing framework Flink sort dynamically analyze data time, thus providing accurate for protection Through training parameter...
The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production immunosuppressive adenosine (ADO) through hydrolysis AMP. is overexpressed many cancers, resulting elevated levels ADO that correspond to poor patient prognosis. Therefore, reducing level via inhibition a potential strategy for treating cancers. Based on binding mode 5′-(α,β-methylene)diphosphate...
Protein B23 (Mr/pI = 38,000/5.1) is a major RNA-associated nucleolar phosphoprotein which contains highly acidic segments and has high affinity for silver ions. Using synthetic oligonucleotides as probes cloned cDNAs encoding protein were isolated characterized. One of the cDNAs, obtained from rat brain library, contained an insert 1232 base pairs DNA polypeptide 292 amino acid residues. Segments sequence confirmed by partial sequencing CNBr fragments hepatoma B23. The methionine-rich...
We employed the suppressive subtractive hybridization to identify 41 up- and downregulated transcripts in Jurkat cells after benzo[a]pyrene (BaP) treatment. Among 21 transcripts, we found that BaP suppresses Keap1 transcript by 7.5-fold. Subsequent analyses revealed significantly message protein levels about 40 60%, respectively, of vehicle controls without reactive oxygen species involvement. In addition, nuclear Nrf2 (nuclear factor erythroid 2-related factor) content is increased...
Herein, we report the discovery and optimization of a series orally bioavailable acyl sulfonamide NaV1.7 inhibitors that are selective for over NaV1.5 highly efficacious in vivo models pain hNaV1.7 target engagement. An analysis physicochemical properties literature suggested sulfonamides with high fsp3 could overcome some pharmacokinetic (PK) efficacy challenges seen existing series. Parallel library syntheses lead to identification analogue 7, which exhibited moderate potency against an...
The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation its role in nociception. In recent years, number aryl and acyl sulfonamides have been reported potent inhibitors NaV1.7, with high selectivity over cardiac isoform NaV1.5. Herein, we report discovery novel series N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)methanesulfonamides selective inhibitors. Starting crystal structure an sulfonamide, rationalized that cyclization to form...
Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement potency through refinement the low energy ligand conformation mitigation high in vivo clearance. An vitro hepatotoxicity hazard identified resolved lipophilicity lipophilic efficiency to arrive at GNE-616 (24), highly potent, metabolically stable, subtype selective inhibitor Nav1.7. Compound 24 showed robust...
Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three kinase isoforms. The discovery of extensive intestinal metabolism major metabolites helped refine design strategy, observed that the pharmacokinetic properties first second was more...
Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant FDA-approved to treat ER+ cancer and works through two mechanisms—as full antagonist selective estrogen degrader (SERD)—but lacks oral bioavailability. Thus, we envisioned "best-in-class" molecule with the same dual mechanisms as fulvestrant, but significant exposure. Through lead optimization, discovered tool 12 (GNE-149) improved degradation antiproliferative activity in both MCF7...