A5012396455- Melanoma and MAPK Pathways
- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Cancer Mechanisms and Therapy
- Genomics and Chromatin Dynamics
- Bacterial Genetics and Biotechnology
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Antibiotic Resistance in Bacteria
- Quinazolinone synthesis and applications
- HER2/EGFR in Cancer Research
- X-ray Diffraction in Crystallography
- Drug Transport and Resistance Mechanisms
- Peptidase Inhibition and Analysis
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- Cytokine Signaling Pathways and Interactions
- Histone Deacetylase Inhibitors Research
- Enzyme Structure and Function
- Lipid Membrane Structure and Behavior
- Protein Tyrosine Phosphatases
EpiCypher (United States)
2022-2024
Array BioPharma (United States)
2008-2014
University of Colorado Boulder
2009
The discovery and optimization of a series 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors protein kinase B/Akt is reported. initial design was guided by the use X-ray structures in complex with Akt1 closely related A. resulting demonstrate potent inhibition all three Akt isoforms biochemical assays poor other members cAMP-dependent kinase/protein G/protein C extended family block phosphorylation multiple downstream targets human cancer cell...
The protein serine-threonine kinase Akt undergoes a substantial conformational change upon activation, which is induced by the phosphorylation of two critical regulatory residues, threonine 308 and serine 473. Paradoxically, treating cells with adenosine 5'-triphosphate (ATP)-competitive inhibitors results in increased both residues. We show that binding ATP-competitive stabilized conformation phosphorylated sites were inaccessible to phosphatases. ATP also produced this protection sites,...
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact N-termini availability the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) linked increased H3K4me3 engagement by BPTF PHD finger, but it unknown if this mechanism has a broader extension. Here, we show that promotes nucleosomal accessibility other H3K4 methyl readers, importantly, extends writers,...
Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated deubiquitinase (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal at target sites protect active genes from aberrant silencing. The subunits (BAP1 ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How establishes specificity for over other nucleosomal ubiquitination how disease-associated mutations of enzyme affect activity unclear. Here, we determine...
During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism which de novo DNA methyltransferase(s) [DNMT(s)] catalyze methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub)....
The V600E mutation of B-Raf kinase results in constitutive activation the MAPK signaling pathway and is present approximately 7% all cancers. Using structure-based design, a novel series pyrazolopyridine inhibitors B-RafV600E was developed. Optimization led to identification 3-methoxy pyrazolopyridines 17 19, potent, selective, orally bioavailable agents that inhibited tumor growth mouse xenograft model driven by with no effect on body weight. On basis their vivo efficacy preliminary safety...
Significance Lipoprotein biosynthesis is crucial for Gram-negative bacterial viability and involves the activities of three essential integral membrane proteins embedded in inner (Lgt, LspA, Lnt). These enzymes function sequentially to produce mature triacylated lipoproteins, many which are then transported outer membrane. Lnt responsible catalyzing addition palmitate N terminus diacylated apolipoproteins. Despite a number studies that have biochemically characterized Escherichia coli Lnt,...
Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type previously described by the authors are potent and but exhibit low solubility requiring use amorphous dispersion-based formulation achieving efficacious drug exposures. Through structure-based design, we discovered a new class highly aminopyrimidine-based with improved pharmacokinetic profiles. The hinge binding moiety possesses basic center...
Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in biogenesis of Gram-negative bacterial lipoproteins which play crucial roles growth and pathogenesis. We demonstrate that Lgt depletion a clinical uropathogenic Escherichia coli strain leads to permeabilization outer membrane increased sensitivity serum killing antibiotics. Importantly, we identify G2824 as first-described inhibitor potently inhibits biochemical activity vitro is bactericidal against wild-type...
Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in clinic is not well understood, because many clinical susceptibility testing approaches lack resolution needed reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor Escherichia coli type II signal peptidase LspA. We demonstrate addition previously known mechanisms resistance LspA inhibitors,...
ABSTRACT Inosine 5′-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step de novo guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target over its human homolog. Here, we show these are bactericidal, generate phenotypic signatures distinct other antibiotics, elicit different time-kill kinetics regulatory responses two important Gram-negative pathogens: Acinetobacter baumannii...
The histidine kinase CheA is a central component of the bacterial chemotaxis signaling cluster, in which transmembrane receptors regulate autokinase activity. homodimer, and each two identical subunits possesses five different domains with distinct structures functions. free enzyme, like receptor-bound catalyzes trans-autokinase reaction catalytic domain (P4) one subunit phosphorylates substrate (P1) other subunit. Molecular analysis motions has important implications for mechanism...