A5101893428- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Synthesis and biological activity
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Cancer-related gene regulation
- Ubiquitin and proteasome pathways
- Genomics and Chromatin Dynamics
- Vitamin C and Antioxidants Research
- Synthetic Organic Chemistry Methods
- RNA modifications and cancer
- Protease and Inhibitor Mechanisms
- Morinda citrifolia extract uses
- Phagocytosis and Immune Regulation
- Boron Compounds in Chemistry
- Chemical Synthesis and Analysis
- Sirtuins and Resveratrol in Medicine
- Signaling Pathways in Disease
- Genetic Neurodegenerative Diseases
- Biochemical and Molecular Research
- Ferroptosis and cancer prognosis
- Synthesis and pharmacology of benzodiazepine derivatives
- Synthesis and Biological Activity
- PI3K/AKT/mTOR signaling in cancer
AbbVie (United States)
2013-2024
Structural Genomics Consortium
2014
University of Toronto
2014
Abbott Fund
2001-2008
Abbott (United Kingdom)
2006
Indiana University Bloomington
1988-1989
Massachusetts Institute of Technology
1986
In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve an efficient hinge-binding template inhibitors. By incorporating N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, series RTK were generated, which potently inhibited activity vascular endothelial growth factor platelet-derived families. A number compounds with oral...
G9a is a histone lysine methyltransferase responsible for the methylation of H3 9. The discovery A-366 arose from unique diversity screening hit, which was optimized by incorporation propyl-pyrrolidine subunit to occupy enzyme channel. potent inhibitor (IC50: 3.3 nM) with greater than 1000-fold selectivity over 21 other methyltransferases.
Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones believed to play an important role in cancer development maintenance. These modifications potentially reversible as a result this class of enzymes has drawn great interest potential therapeutic targets small molecule inhibitors. Previous studies have suggested the histone methyltransferase G9a (EHMT2) is required perpetuate malignant phenotypes through multiple mechanisms variety...
p300 and its paralog CBP can acetylate histones other proteins have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has identified through virtual ligand screening subsequent optimization unique hydantoin hit. Conformational restraint the form spirocyclization followed substitution with urea led to significant improvement potency. Replacement...
The NMR-based discovery of biaryl hydroxamate inhibitors the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these exhibited no vivo activity due, at least part, to poor pharmacokinetic properties alkylhydroxamate moiety. To circumvent this liability, screening was implemented identify alternative zinc-chelating groups. Using technique, 1-naphthyl found bind tightly protein (K(D) = 50...
Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target anticancer therapy. Known NAMPT inhibitors with potent cell activity composed nitrogen-containing aromatic group, which is phosphoribosylated by enzyme. Here, we identified two novel types...
Aberrant gene activation driven by the histone acetyltransferases p300 and CREB binding protein (CBP) has been linked to several diseases, including cancers. Because of this, many efforts have aimed toward targeting closely related paralogues, CBP, but these endeavors exclusively directed noncovalent inhibitors. X-ray crystallography A-485 revealed that both CBP possess a cysteine (C1450) near active site, thus rendering covalent inhibition an attractive chemical approach. Herein we report...
TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the microenvironment. Inhibiting MerTK Axl selectively is believed hinder cell survival, reverse protumor myeloid phenotype, suppress efferocytosis, thereby eliciting an immune response. In this study, we present discovery
Inhibition of the receptor tyrosine kinase MerTK by small molecules has potential to augment immune response tumors. Potent, selective inhibitors with high levels
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to phase I clinical trial for the treatment of multiple myeloma. Due its large size structural complexity, challenging synthetic target. Herein, we describe synthesis on decagram scale, which enabled preclinical characterization. The strategy convergent stereoselective, featuring hindered biaryl cross coupling, enantioselective hydrogenation, conformationally preorganized macrocyclization by C–O bond formation as key steps.