A5016595929- DNA Repair Mechanisms
- Bacterial Genetics and Biotechnology
- Cancer-related gene regulation
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- Wnt/β-catenin signaling in development and cancer
- Neurological diseases and metabolism
- Enzyme Structure and Function
- X-ray Diffraction in Crystallography
- Carbohydrate Chemistry and Synthesis
- RNA regulation and disease
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- Antenna Design and Analysis
- Microbial Metabolism and Applications
- Chemical Synthesis and Analysis
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Polyomavirus and related diseases
- Viral gastroenteritis research and epidemiology
- Hepatitis Viruses Studies and Epidemiology
Novartis (United States)
2009-2021
Novartis (Switzerland)
2011-2019
Novartis Institutes for BioMedical Research
2011-2019
Geophysical Laboratory
2015
Abbott Fund
1998-1999
Duke Medical Center
1995-1996
Duke University
1992-1996
Duke University Hospital
1995-1996
Northwestern University
1992
A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors the fibroblast growth factor receptor tyrosine kinases 1, 2, 3 by rationally designing substitution pattern aryl ring. On basis its in vitro profile, compound 1h (NVP-BGJ398) was selected for vivo evaluation showed significant antitumor activity RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support potential therapeutic use as a new anticancer agent.
Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety human cancers. Herein we describe structure guided optimization series 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where pharmacokinetic properties were improved by modulating electronics 6-position heterocycle, and overall druglike fine-tuned further modification 4-position substituent. The resulting 2,4-bismorpholino potent class I PI3K...
The prevalent mechanism of bacterial resistance to erythromycin and other antibiotics the macrolide-lincosamide-streptogramin B group (MLS) is methylation 23S rRNA component 50S subunit in ribosomes. This sequence-specific catalyzed by Erm methyltransferases (MTases). They are found several strains pathogenic bacteria, ErmC most studied member this class. crystal structure ErmC' (a naturally occurring variant ErmC) from Bacillus subtilis has been determined at 3.0 A resolution multiple...
PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 histone H3, leading to chromatin compaction repression tumor suppressor genes. Inhibiting this activity by small molecules targeting was shown result antitumor efficacy. Here, we describe the optimization chemical series representing new class inhibitors which acts allosterically via trimethyllysine pocket...
Polycomb repressive complex 2 (PRC2), a histone H3 lysine 27 methyltransferase, plays key role in gene regulation and is known epigenetics drug target for cancer therapy. The WD40 domain-containing protein EED the regulatory subunit of PRC2. It binds to tri-methylated (H3K27me3), through which stimulates activity PRC2 allosterically. Recently, we disclosed novel inhibitor EED226 K27me3-pocket on showed strong antitumor xenograft mice model. Here, further report identification validation four...
Vancomycin-resistant enterococci are pathogenic bacteria that have altered cell-wall peptidoglycan termini (D-alanyl-D-lactate [D-Ala-D-lactate] instead of D-alanyl-D-alanine [D-Ala-D-Ala]), which results in a 1000-fold decreased affinity for binding vancomycin. The metallodipeptidase VanX (EntVanX) is key enzyme antibiotic resistance as it reduces the cellular pool D-Ala-D-Ala dipeptide.A bacterial genome search revealed vanX homologs Streptomyces toyocaensis (StoVanX), Escherichia coli...
In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes explore wide variety substitution patterns and convergently access diverse array analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from exploration heterocycles at the C-5 position, phenyl groups C-4,...
The lip gene of Escherichia coli has been cloned and sequenced. Subcloning a 3-kilobase EcoRI/EcoRV restriction fragment from Clark-Carbon plasmid pLC15-5 into pUC18 gives that complements two lipoate auxotrophs, W1485-lip2 JRG33-lip9, which expresses protein approximately 36,000 Da. Sequencing suggests codes for 281 amino acids (31,350 Da), showing sequence similarity to biotin synthase. It is thus likely encodes sulfur insertion enzyme analogous synthase the chemistries systems are...
RAS mutations lead to a constitutively active oncogenic protein that signals through multiple effector pathways. In this chemical biology study, we describe novel coupled biochemical assay measures activation of the BRAF by prenylated KRASG12V in lipid-dependent manner. Using assay, discovered compounds block and cellular functions with low single-digit micromolar potency. We characterized structural basis for inhibition using NMR methods showed stabilized inactive conformation KRASG12V....
Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates resistance, driven largely by target-based mutations in the GyrA/ParC resistance determining region, eroded utility threaten future use this vital class antibiotics. Herein we describe optimization a series 4-(aminomethyl)quinolin-2(1H)-ones, exemplified 34, inhibit IV...
ATR, a protein kinase in the PIKK family, plays critical role cell DNA-damage response and is an attractive anticancer drug target. Several potent selective inhibitors of ATR have been reported showing significant antitumor efficacy, with most advanced ones entering clinical trials. However, due to absence experimental structure, determinants contributing inhibitors' potency specificity are not well understood. Here we present mutations ATP-binding site PI3Kα progressively transform pocket...
Abstract Influenza virus uses a unique mechanism to initiate viral transcription named cap-snatching. The PB2 subunit of the heterotrimeric RNA polymerase binds cap structure cellular pre-mRNA promote its cleavage by PA subunit. resulting 11–13 capped oligomer is used PB1 proteins. VX-787 an inhibitor influenza A cap-binding protein PB2. This clinical stage compound was shown bind minimal domain inhibit cap-snatching machinery. However, binding this molecule in context extended form has...
Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase topoisomerase IV via binding to, stabilization of, cleavage complexes. Optimization this led to identification compound 25, which has potent activity against Gram-positive bacteria, favorable in vitro safety profile, excellent vivo pharmacokinetic properties. Compound 25 was found be efficacious fluoroquinolone-sensitive Staphylococcus aureus infection mouse thigh model at lower doses than...