The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in a variety of human cancers. We have identified a novel series of pyrazolylpyrroles as inhibitors of ERK. Aided by the discovery of two distinct binding modes for the pyrazolylpyrrole scaffold, structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor of ERK.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm061381f | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Flipping the substrate preference of Hazara virus ovarian tumour domain protease through structure-based mutagenesis.
Acta Crystallogr D Struct Biol
November 2020
Pharmaceutical and Biomedical Sciences, University of Georgia, 240 West Green Street, Athens, GA 30602, USA.
Nairoviruses are arthropod-borne viruses with a nearly global geographical distribution. Several are known causative agents of human disease, including Crimean-Congo hemorrhagic fever virus (CCHFV), which has a case fatality rate that can exceed 30%. Nairoviruses encode an ovarian tumour domain protease (OTU) that can suppress the innate immune response by reversing post-translational modifications by ubiquitin (Ub) and/or interferon-stimulated gene product 15 (ISG15).
View Article and Find Full Text PDFStructure-Guided Design of a Peptide Lock for Modular Peptide Binders.
ACS Chem Biol
February 2020
Department of Biochemistry , University Zürich, Winterthurerstrasse 190 , 8057 Zürich , Switzerland.
Peptides play an important role in intermolecular interactions and are frequent analytes in diagnostic assays, also as unstructured, linear epitopes in whole proteins. Yet, due to the many different sequence possibilities even for short peptides, classical selection of binding proteins from a library, one at a time, is not scalable to proteomes. However, moving away from selection to a rational assembly of preselected modules binding to predefined linear epitopes would split the problem into smaller parts.
View Article and Find Full Text PDFStructures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity.
Nat Struct Mol Biol
May 2016
Department of Chemistry, University of California, Davis, Davis, California, USA.
Adenosine deaminases acting on RNA (ADARs) are editing enzymes that convert adenosine to inosine in duplex RNA, a modification reaction with wide-ranging consequences in RNA function. Understanding of the ADAR reaction mechanism, the origin of editing-site selectivity, and the effect of mutations is limited by the lack of high-resolution structural data for complexes of ADARs bound to substrate RNAs. Here we describe four crystal structures of the human ADAR2 deaminase domain bound to RNA duplexes bearing a mimic of the deamination reaction intermediate.
View Article and Find Full Text PDFCo-operative and Hierarchical Binding of c-FLIP and Caspase-8: A Unified Model Defines How c-FLIP Isoforms Differentially Control Cell Fate.
Mol Cell
March 2016
MRC Toxicology Unit, Hodgkin Building, P.O. Box 138, Lancaster Road, Leicester LE1 9HN, UK. Electronic address:
The death-inducing signaling complex (DISC) initiates death receptor-induced apoptosis. DISC assembly and activation are controlled by c-FLIP isoforms, which function as pro-apoptotic (c-FLIPL only) or anti-apoptotic (c-FLIPL/c-FLIPS) regulators of procaspase-8 activation. Current models assume that c-FLIP directly competes with procaspase-8 for recruitment to FADD.
View Article and Find Full Text PDFCrystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition.
J Biol Chem
April 2014
State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing 100193, China. Electronic address:
N(6)-Methylation of adenosine is the most ubiquitous and abundant modification of nucleoside in eukaryotic mRNA and long non-coding RNA. This modification plays an essential role in the regulation of mRNA translation and RNA metabolism. Recently, human AlkB homolog 5 (Alkbh5) and fat mass- and obesity-associated protein (FTO) were shown to erase this methyl modification on mRNA.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!