A5091393843- Chronic Myeloid Leukemia Treatments
- Lung Cancer Treatments and Mutations
- Chronic Lymphocytic Leukemia Research
- Lymphoma Diagnosis and Treatment
- HER2/EGFR in Cancer Research
- Cancer-related gene regulation
- Cancer therapeutics and mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Melanoma and MAPK Pathways
- Pluripotent Stem Cells Research
- Lung Cancer Research Studies
- Axon Guidance and Neuronal Signaling
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Parkinson's Disease Mechanisms and Treatments
- CRISPR and Genetic Engineering
- Quinazolinone synthesis and applications
- Muscle activation and electromyography studies
- Plant Gene Expression Analysis
- Synthesis and Catalytic Reactions
- Synthesis and biological activity
- Diabetic Foot Ulcer Assessment and Management
- Cancer-related Molecular Pathways
- Cancer Mechanisms and Therapy
- Acute Myeloid Leukemia Research
Seoul National University
2024
University of Central Florida
2021-2023
Dana-Farber Cancer Institute
2012-2023
Daegu-Gyeongbuk Medical Innovation Foundation
2016-2022
Stony Brook University
2021
Korea Institute of Science and Technology
2010-2021
Harvard University
2011-2020
Dongguk University
2014-2020
Michigan United
2020
Sogang University
2010-2011
Abstract Purpose: The EML4-ALK fusion gene has been detected in ∼7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency Caucasian NSCLC and lines. also whether TAE684, a specific ALK kinase inhibitor, would inhibit growth EML4-ALK-containing lines vitro vivo. Experimental Design: screened 305 primary [both U.S. (n = 138) Korean 167) patients] 83 using reverse transcription-PCR by exon array analyses. evaluated efficacy TAE684 against Results: four different variants,...
Abstract Selective kinase inhibitors have had a substantial impact on the field of medical oncology. Whereas these agents can elicit dramatic clinical responses in some settings, their activity is generally limited to subset treated patients whose tumor cells harbor specific genetic lesion. We established an automated platform for examining sensitivity various molecularly targeted across large panel human tumor-derived cell lines identify additional genotype-correlated that may be clinically...
Abstract Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models lung cancer patients harboring the T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired to this class of inhibitors. We sought identify study mutations that confer agents. Experimental Design: performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen EGFR-mutant (sensitizing...
Abstract We report the synthesis of a GDP analogue, SML‐8‐73‐1, and prodrug derivative, SML‐10‐70‐1, which are selective, direct‐acting covalent inhibitors K‐Ras G12C mutant relative to wild‐type Ras. Biochemical biophysical measurements suggest that modification with SML‐8‐73‐1 renders protein in an inactive state. These first‐in‐class demonstrate irreversible targeting guanine‐nucleotide binding site is potentially viable therapeutic strategy for inhibition Ras signaling.
Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators combat invading pathogens respond tissue damage in host, whereas regulatory (M2b) high levels anti-inflammatory molecules, such as IL-10, low cytokines, like IL-12, are important for inflammatory responses. A central problem this area is understand how formation can...
Significance SML-8-73-1 (SML) is the first example, to our knowledge, of a GTP-competitive inhibitor V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras). A high-resolution structure K-Ras G12C bound SML shows in an inactive conformation. In situ proteomic-based chemical profiling demonstrates that highly selective for over other small GTPases. novel chemosensor-based assay allows measurement covalent reaction rates between and enables characterization this context millimolar...
The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, invasion. Here we report the discovery of a potent selective inhibitor, DDR1-IN-1, present 2.2 Å co-crystal structure. DDR1-IN-1 binds to 'DFG-out' conformation inhibits autophosphorylation cells at submicromolar concentrations with good selectivity assessed against panel 451 kinases measured using KinomeScan...
Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report 2-anilino-4-methylamino-5-chloropyrimidine, HG-10-102-01(4) is potent selective inhibitor wild-type LRRK2 the G2019S mutant. Compound 4 substantially inhibits Ser910 Ser935 phosphorylation both mutant at concentration 0.1-0.3 µM cells first compound reported to be capable inhibiting mouse brain following...
Abstract BRAFV600E is the most common oncogenic lesion in melanoma and results constitutive activation of MAPK pathway uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize signaling, restrain cellular growth, improve patient outcome. Although several mechanisms resistance described, directed solutions overcome these lesions are still lacking. Herein, we found that can be (i) mediated by EPHA2, a member largest receptor tyrosine kinases (RTK)...
AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose EGFR T790M remains unclear. Here, we report unbiased, atomic-level molecular dynamics (MD) simulations which spontaneous association kinases having WT and mutant gatekeepers was observed. Simulation-generated structural models suggest that differs from WT, interacts extensively gatekeeper...
Heart disease involves irreversible myocardial injury that leads to high morbidity and mortality rates. Numerous cell-based cardiac in vitro models have been proposed as complementary approaches non-clinical animal research. However, most of these struggle accurately replicate adult human heart conditions, such infarction ventricular remodeling pathology. The intricate interplay between various cell types within the heart, including cardiomyocytes, fibroblasts, endothelial cells, contributes...
Significance IL-10 plays an essential role in maintaining gut immune homeostasis as evidenced by the link between genetic perturbation of this anti-inflammatory cytokine and inflammatory bowel disease (IBD). Here, we describe a small-molecule screen that identified inhibition salt-inducible kinases (SIKs) strategy to enhance production macrophages dendritic cells. Significantly, IL-10–potentiating effects SIK are associated with reduced secretion cytokines IL-1β, IL-6, IL-12, TNF-α, these...
Efficient and precise genetic engineering in livestock such as cattle holds great promise agriculture biomedicine. However, techniques that generate pluripotent stem cells, well reliable tools for gene targeting livestock, are still inefficient, thus not routinely used. Here, we report highly efficient the bovine genome using cells clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 nuclease. First, induced (iPSCs) from somatic fibroblasts by ectopic expression of yamanaka...
Salt-inducible kinases (SIKs) are promising therapeutic targets for modulating cytokine responses during innate immune activation. The study of SIK inhibition in animal models disease has been limited by the lack selective small-molecule probes suitable function vivo. We used pan-SIK inhibitor HG-9-91-01 as a starting point to develop improved analogs, yielding novel probe 5 (YKL-05-099) that displays increased selectivity SIKs versus other and enhanced pharmacokinetic properties....
Ras proteins are members of a large family GTPase enzymes that commonly mutated in cancer where they act as dominant oncogenes. We previously developed an irreversible guanosine-derived inhibitor, SML-8-73-1, mutant G12C RAS forms covalent bond with cysteine 12. Here we report exploration the structure–activity relationships (SAR) hydrolytically stable analogues SML-8-73-1 KRAS inhibitors. discovery difluoromethylene bisphosphonate such compound 11, which, despite exhibiting reduced...
The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II inhibitor 2 (GNF-7), based upon 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable potently inhibiting wild-type as well other clinically relevant mutants such G250E, Q252H, Y253H, E255K, E255V, F317L, M351T in biochemical cellular assays. In addition, compound...