A5054645918- Osteoarthritis Treatment and Mechanisms
- Tendon Structure and Treatment
- Malaria Research and Control
- RNA Research and Splicing
- Mosquito-borne diseases and control
- Shoulder Injury and Treatment
- Wnt/β-catenin signaling in development and cancer
- Computational Drug Discovery Methods
- Immune Response and Inflammation
- Inflammatory mediators and NSAID effects
- Knee injuries and reconstruction techniques
- Peptidase Inhibition and Analysis
- Dupuytren's Contracture and Treatments
- Fibromyalgia and Chronic Fatigue Syndrome Research
- Lymphoma Diagnosis and Treatment
- Helminth infection and control
- Synthesis and Catalytic Reactions
- NF-κB Signaling Pathways
- PI3K/AKT/mTOR signaling in cancer
- Down syndrome and intellectual disability research
- T-cell and B-cell Immunology
- Antimicrobial Peptides and Activities
- Plant and fungal interactions
- Plant Toxicity and Pharmacological Properties
- Parasites and Host Interactions
Fate Therapeutics (United States)
2024
Samumed (United States)
2017-2020
Genomics Institute of the Novartis Research Foundation
2013-2020
University of California, San Diego
2001
Harvard University
1999
<h2>Summary</h2><h3>Objectives</h3> Osteoarthritis (OA) is a degenerative disease characterized by loss of cartilage and increased subchondral bone within synovial joints. Wnt signaling affects the pathogenesis OA as this pathway modulates both differentiation osteoblasts chondrocytes, production catabolic proteases. A novel small-molecule inhibitor, SM04690, was evaluated in series <i>in vitro</i> vivo</i> animal studies to determine its effects on chondrogenesis, protection synovial-lined...
ObjectivesWnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis cartilage protection in an animal OA model, was evaluated elucidate its mechanism of action.DesignBiochemical assays measured kinase activity. Western blots protein phosphorylation human mesenchymal stem cells (hMSCs), chondrocytes,...
To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 showed a half-maximal inhibitory concentration less 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well other series associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific...
The Wnt/β-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a small molecule clinical development the treatment of solid tumors, was shown reduce Wnt gene expression through potent inhibition CDC-like kinase (CLK) activity. SM08502 inhibited serine arginine rich splicing factor (SRSF) phosphorylation disrupted spliceosome activity, which...
In order to identify the most attractive starting points for drugs that can be used prevent malaria, a diverse chemical space comprising tens of thousands millions small molecules may need examined. Achieving this throughput necessitates development efficient ultra-high-throughput screening methods. Here, we report and evaluation luciferase-based phenotypic screen malaria exoerythrocytic-stage parasites optimized 1536-well format. This assay uses exoerythrocytic stage rodent parasite,...
Abstract The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role this signaling may be a relevant target for treatment. current study examined the therapeutic of SM04755, topical, small‐molecule inhibitor, treatment tendinopathy using vitro assays animal models. In vitro, SM04755 decreased activity, induced differentiation, inhibited catabolic enzymes pro‐inflammatory cytokines human mesenchymal stem cells, rat...
Nitric oxide (NO), a free radical gas whose production is catalyzed by the enzyme NO synthase, participates in regulation of multiple organ systems. The inducible isoform synthase (iNOS) transcriptionally up-regulated inflammatory stimuli; critical mediator this process nuclear factor (NF)-κB. Our objective was to determine which regulatory elements other than NF-κB binding sites are important for activation iNOS promoter/enhancer. We also wanted identify transcription factors that may be...
ABSTRACT Hookworm infection is a major cause of iron deficiency anemia and malnutrition in developing countries. The Ancylostoma ceylanicum Kunitz-type inhibitor (AceKI) 7.9-kDa broad-spectrum trypsin, chymotrypsin, pancreatic elastase that has previously been isolated from adult hookworms. Site-directed mutagenesis the predicted P1 inhibitory reactive site amino acid confirmed role Met 26 mediating inhibition three target serine proteases. By using reverse transcription-PCR, it was...
Abnormal Wnt signaling in intervertebral discs (IVDs) progresses degenerative disc disease (DDD) pathogenesis by impairing nucleus pulposus cell function, decreasing matrix deposition, and accelerating fibrosis.This study was conducted to evaluate the effects of lorecivivint (LOR; SM04690), a small-molecule pathway inhibitor, on IVD cells an animal model DDD.We used vitro assays rat DDD test LOR senescence viability, annulus fibrosus (AF) fibrosis, cartilage regeneration protection.Wnt gene...
Abstract Background: The dual-specificity tyrosine-regulated kinase 1A (DYRK1A) can phosphorylate multiple targets involved in key cellular processes that have been associated with the hallmarks of cancer, including proliferation, survival, cell cycle regulation and DNA damage response1. In addition, compounds inhibit DYRK1A demonstrated anti-tumor activity both vitro vivo. However, until recently, there was a paucity potent, specific, bioavailable inhibitors did not target related cdc2-like...
Abstract BACKGROUND: AKT1 E17K is a clinically validated oncogenic driver mutated in ~1-2% of all cancers and enriched several solid tumors including breast (~5%), endometrial (~3%) prostate (~1.5%) cancer. Over half mutant gynecologic are homozygous for the oncogene with loss wildtype (WT) allele via copy-neutral loss-of-heterozygosity (CN-LOH), suggesting uniquely potent addiction these tumor types. While inhibitors WT PI3K or AKT have demonstrated clinical efficacy HR+/HER2- metastatic...
<h3>Background</h3> Osteoarthritis (OA) is characterized by pain, deformity, and reduced function in the knee joint. Upregulated Wnt signaling affects pathogenesis of OA through increased inflammation, subchondral bone thinning cartilage. SM04690, a novel small molecule, was previously shown to inhibit pathway induce chondrogenesis <i>in vitro</i> vivo.</i><sup>1</sup> <h3>Objectives</h3> SM04690 evaluated preclinical studies determine its capacity reduce pain OA. <h3>Methods</h3>...
Abstract Dysregulated alternative pre-mRNA splicing (AS) is commonly associated with human malignancies, producing pathological proteomes that underlie disease initiation, progression, and therapeutic resistance. The CDC2-like kinases (CLKs) dual-specificity tyrosine-regulated (DYRKs) are thought to govern AS efficiency specificity by directly phosphorylating factors influence splice junction selection. Cirtuvivint (SM08502) a first-in-class small molecule ATP-competitive inhibitor of...
<h3>Background</h3> Tendinopathy is an inflammatory and degenerative disorder caused by injuries or overuse. It can progress to a chronic condition with failed healing, tendon fibrosis micro-tears that lead pain sometimes rupture. Current therapeutic options focus mainly on relief rather than treatment of underlying disease. The Wnt pathway upregulated in tendinopathy has important role inflammation, tenocyte differentiation. <h3>Objectives</h3> SM04755, novel, topical inhibitor, was...
<h3>Background</h3> In the synovial joint, Wnt pathway upregulation contributes to osteoarthritis (OA) by increasing osteocyte differentiation, cartilage thinning, and inflammation. SM04690, a novel small molecule, has previously demonstrated potential OA disease-modifying effects through inhibition <i>in vitro</i> vivo</i>. <h3>Objectives</h3> To elucidate mechanism of action for SM04690 on inhibition, chondrocyte anti-inflammation. <h3>Methods</h3> activity was measured using cell-based...