A5100728619- Epigenetics and DNA Methylation
- Glioma Diagnosis and Treatment
- Cancer-related gene regulation
- X-ray Diffraction in Crystallography
- Biochemical and Molecular Research
- Crystallization and Solubility Studies
- Histone Deacetylase Inhibitors Research
- Acute Myeloid Leukemia Research
- Plant biochemistry and biosynthesis
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- Asymmetric Synthesis and Catalysis
- Malaria Research and Control
- Viral gastroenteritis research and epidemiology
- Genomics and Chromatin Dynamics
- Viral Infections and Vectors
- Enzyme Structure and Function
- Mosquito-borne diseases and control
- Viral Infections and Immunology Research
- HIV/AIDS drug development and treatment
- Ubiquitin and proteasome pathways
- Bone health and treatments
- RNA modifications and cancer
- Synthetic Organic Chemistry Methods
- Virus-based gene therapy research
Baylor College of Medicine
2016-2025
Wuhan University
2023
Xihua University
2021-2023
Shihezi University
2023
Thermo Fisher Scientific (United States)
2023
Division of Chemistry
2021
Dalian University of Technology
2020
Gansu Agricultural University
2018
Cancer Center Amsterdam
2017
Mayo Clinic in Arizona
2017
Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. posing a serious public health threat. The golden carotenoid pigment of aureus, staphyloxanthin, promotes resistance to reactive oxygen species host neutrophil-based killing, early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural...
Abstract The copper‐catalyzed radical aminofluorination of styrenes with N‐fluorobenzenesulfonimide (NFSI) is realized high regioselectivity, thus affording products regioselectivities opposite that the palladium‐catalyzed and noncatalyzed processes. Preliminary mechanistic studies suggested reaction went through a pathway was supported by DFT calculations. In these reactions, NFSI utilized as both nitrogen source fluorine source, rendering it an attractive reagent.
Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and geranylgeranyl (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition diphosphate synthase (FPPS) (GGPPS), two enzymes upstream FTase GGTase, by lipophilic bisphosphonates. Due to dual site targeting decreased polarity, compounds have activities far greater than do current bisphosphonate drugs in inhibiting...
Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl (GGPPS), as well undecaprenyl (UPPS), a cis-prenyltransferase interest target for antibacterial therapy. Our results on GGPPS (10 structures) there three bisphosphonate-binding sites, consisting FPP or isopentenyl substrate-binding sites...
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs many patients. ER still plays critical role the growth of cancer cells with acquired resistance, suggesting that ERα remains valid target tamoxifen-resistant (Tam-R) cancer. In an effort identify novel regulators signaling, through small-scale siRNA screen against histone methyl modifiers, we found WHSC1, H3K36 methyltransferase, as...
Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Apicomplexan parasites contain a relict chloroplast, apicoplast. The apicoplast is indispensable an attractive drug target. home to 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for synthesis isoprenoid precursors. This believed be most conserved function apicoplast, fosmidomycin, specific inhibitor pathway, effective antimalarial. Surprisingly, fosmidomycin has no effect...
Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors with IC50 values low 38 nM. These exhibit only weak or no activities against four other representative histone lysine arginine methyltransferases, G9a, SUV39H1, PRMT1 CARM1. The X-ray crystal structure a DOT1L–inhibitor complex reveals that the N6-methyl group...
Significance Androgen receptor (AR) signaling is a key driver of prostate cancer (PC), even in the context resistance to current therapies, creating an unmet need for novel approaches inhibit AR. We demonstrate that transcription factor GATA-binding protein 2 (GATA2) critical both AR expression and optimal transcriptional activity. GATA2 colocalizes with Forkhead box A1 on chromatin enhance recruitment steroid coactivators formation holocomplex. A inhibitor suppressed function (including...
Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for replication therefore a drug target. Compound screening followed by medicinal chemistry yielded series of drug-like, broadly active inhibitors proteases with IC50 as low 120 nM. inhibitor exhibited significant antiviral activities in cells (EC68: 300-600 nM)...
Mixed lineage leukemia (MLL) gene translocations are found in ~75 % infant and 10 adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged needed. were examined their biochemical biological activities as well other cancer cells. Potent with IC50 values 9.8–77 nM strongly inhibit proliferation cells EC50 10–320 nM, while...
While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), inhibitor is yet to enter the clinic. We used scaffold C188, small-molecule previously identified by us, in hit-to-lead program identify C188-9. C188-9 binds with high affinity represents substantial improvement over C188 its ability inhibit binding pY-peptide ligand, cytokine-stimulated pSTAT3, reduce constitutive pSTAT3 activity multiple HNSCC lines, anchorage...
The gold color of Staphylococcus aureus is derived from the carotenoid staphyloxanthin, a virulence factor for organism. Here, we report synthesis and activity broad variety staphyloxanthin biosynthesis inhibitors that inhibit first committed step in its biosynthesis, condensation two farnesyl diphosphate (FPP) molecules to dehydrosqualene, catalyzed by enzyme dehydrosqualene synthase (CrtM). most active compounds are phosphonoacetamides have low nanomolar K(i) values CrtM inhibition whole...
// Li Zhang 1 , Lisheng Deng Fengju Chen 2 Yuan Yao Bulan Wu Liping Wei Qianxing Mo 2, 3 Yongcheng Song 1, Department of Pharmacology, Baylor College Medicine, Houston, TX 77030, USA Dan L. Duncan Cancer Center, Section Hematology/Oncology, Correspondence to: Song, e-mail: ysong@bcm.edu Keywords: DOT1L, histone methylation, inhibitor, breast cancer, cancer stem cell Received: May 30, 2014 Accepted: September 16, Published: November 10, ABSTRACT Histone lysine methylation regulates gene...
Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent inhibitors identified Ki values as low 0.5 nM. These also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure–activity relationships (SAR) these their inhibitory activities against are discussed....
Methylation of histone lysine residues plays important roles in gene expression regulation as well cancer initiation. Lysine specific demethylase 1 (LSD1) is responsible for maintaining balanced methylation levels at H3 4 (H3K4). LSD1 a drug target certain cancers, due to functions methylated H3K4 or overexpression. We report the design, synthesis, and structure–activity relationships 3-(piperidin-4-ylmethoxy)pyridine containing compounds potent inhibitors with Ki values low 29 nM. These...
Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity wild-type IDH1, R132H and R132C mutant proteins can reduce α-ketoglutaric acid (α-KG) to d-2-hydroxyglutaric (D2HG). The resulting high concentration D2HG inhibits many α-KG-dependent dioxygenases, including histone demethylases, cause broad hypermethylation. These aberrant epigenetic changes responsible for initiation these cancers. We report...
DOT1L, the only known histone H3-lysine 79 (H3K79) methyltransferase, has been shown to be essential for survival and proliferation of mixed-linkage leukemia (MLL) gene rearranged cells, which are often resistant conventional chemotherapeutic agents. To study functions DOT1L in MLL-rearranged leukemia, SYC-522, a potent inhibitor developed our laboratory, was used treat cell lines patient samples. SYC-522 significantly inhibited methylation at H3K79, but not H3K4 or H3K27, decreased...
Sea buckthorn pomace is a by-product of sea products that not effectively utilized. This study obtained polysaccharides (SPs) from pomace, analyzed its structure, and investigated regulatory effect on the gut microbiota imbalance induced by cefixime. The results showed SPs had an average molecular weight 6.26 × 103 kDa mainly consisted galacturonic acid, galactose, rhamnose. Biochemical analysis increased concentration short-chain fatty acids (SCFAs) abundance Proteobacteria,...