A5039712740- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- RNA and protein synthesis mechanisms
- Ubiquitin and proteasome pathways
- Plant-Microbe Interactions and Immunity
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Polyamine Metabolism and Applications
- Cancer-related gene regulation
- HIV/AIDS drug development and treatment
- Bacteriophages and microbial interactions
- Cell death mechanisms and regulation
- Metabolism and Genetic Disorders
- Arsenic contamination and mitigation
- Plant Pathogenic Bacteria Studies
- Cancer therapeutics and mechanisms
- Natural Compounds in Disease Treatment
- RNA modifications and cancer
- Protein Hydrolysis and Bioactive Peptides
- Photosynthetic Processes and Mechanisms
- Sphingolipid Metabolism and Signaling
- Cancer Cells and Metastasis
- Bacterial Genetics and Biotechnology
University of California, San Francisco
2019-2020
University of California, Irvine
2020
Amgen (United States)
2014
Academia Sinica
2000-2003
University of British Columbia
1994-1997
University of Guelph
1997
Georgetown University
1992
University of Washington
1992
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor MDM2-p53 interaction. Continued research investigation N-alkyl substituent this series, focused in particular on previously underutilized interaction shallow cleft MDM2 surface, led to one-carbon tethered sulfone which gave rise substantial improvements biochemical cellular potency. Further produced AMG 232 (2), is currently being evaluated human clinical trials for treatment cancer. Compound 2...
Previously we reported the purification of heparin-binding growth factor pleiotrophin (PTN) from supernatants human breast cancer cell line MDA-MB-231. To investigate further biological activities PTN and its potential role in cancer, cloned a cDNA expressed gene kidney adrenal carcinoma (SW-13). The harvested cells transfected with contained specific protein an apparent molecular mass 18 kDa. These stimulated proliferation endothelial as well anchorage-independent SW-13 normal rat...
Structure-based rational design led to the discovery of novel inhibitors MDM2–p53 protein–protein interaction. The affinity these compounds for MDM2 was improved through conformational control both piperidinone ring and appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent selective inhibitor with excellent pharmacokinetic properties in vivo efficacy.
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor MDM2–p53 interaction. Our continued search for diverse analogues led to novel morpholinone MDM2 inhibitors. This change core has significant impact on both potency metabolic stability compared series. Within this series, AM-8735 emerged as an with remarkable biochemical (HTRF IC50 = 0.4 nM) cellular (SJSA-1 EdU 25 nM), well pharmacokinetic properties. Compound 4 also shows excellent...
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led design synthesis tetrasubstituted morpholinone 10, an inhibitor with a biochemical IC50 1.0 μM. The cocrystal structure 10 inspired two independent optimization strategies resulted in discovery morpholinones 16 27 possessing distinct binding modes. Both analogues were potent inhibitors cellular assays, (IC50 = 0.10 μM) also displayed suitable PK profile for vivo animal...
We previously reported the discovery of potent and selective morpholinone piperidinone inhibitors MDM2-p53 interaction. These have in common a carboxylic acid moiety that engages an electrostatic interaction with MDM2-His96. Our continued search for diverse led to novel replacements these acids uncovering new interactions MDM2 protein. In particular, using pyridine or thiazole as isosteres resulted very analogues. From these, AM-6761 (4) emerged inhibitor remarkable biochemical (HTRF IC50 =...
The wbp gene cluster, encoding the B-band lipopolysaccharide O antigen of Pseudomonas aeruginosa serotype O5 strain PAO1, was previously shown to contain a wzy (rfc) O-antigen polymerase. This study describes molecular characterization corresponding wzz (rol) gene, responsible for modulating chain length. P. Wzz has 19 20% amino acid identity with Escherichia coli, Salmonella enterica, and Shigella flexneri. Knockout mutations in serotypes O16 (which an structurally related that O5) yielded...
Continued optimization of the N-substituent in piperidinone series provided potent piperidinone–pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties rats. Reducing structure complexity N-alkyl substituent led to discovery 23, a simplified inhibitor MDM2. Compound 23 exhibits excellent substantial vivo antitumor activity SJSA-1 osteosarcoma xenograft mouse model.
Targeting the inability of cancerous cells to adapt metabolic stress is a promising alternative conventional cancer chemotherapy. FTY720 (Gilenya), an FDA-approved drug for treatment multiple sclerosis, has recently been shown inhibit progression through down-regulation essential nutrient transport proteins, selectively starving death. However, clinical use therapy prohibited because its capability inducing immunosuppression (lymphopenia) and bradycardia when phosphorylated upon...
In vitro drug metabolism studies during the early discovery stage are becoming increasingly important. With increasing demand for high throughput and quick turnaround time in studies, however, careful examination of results proper design experiments still crucial. this communication, we report identification mechanism formation a novel metabonate from incubations diamine-containing compound with liver microsomes. The appeared to be major product, its was NADPH- microsomal protein-dependent....
A proteinase secreted by the sapstaining fungus Ophiostoma piceae is thought to be necessary for primary retrieval of nitrogen from wood proteins. By using mass spectrometry (MS) techniques, we have established cleavage specificity this subtilisin-like serine proteinase. This work demonstrated potential MS in determining specificities newly isolated proteinases a relatively short time frame, and determined that O. showed substrate similar K. Primary insulin B-chain occurred between Leu15...
Natural products serve as chemical blueprints for the majority of classes antibiotics in our clinical arsenal. The evolutionary process by which these molecules arise is inherently accompanied co-evolution resistance mechanisms that shorten lifetime any given class. Virginiamycin acetyltransferases (Vats) are proteins provide protection against streptogramins, potent Gram-positive inhibit bacterial ribosome. Due to challenge selectively modifying chemically complex, 23-membered macrocyclic...