A5016866989- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Multiple Myeloma Research and Treatments
- CAR-T cell therapy research
- Histone Deacetylase Inhibitors Research
- Signaling Pathways in Disease
- Prostate Cancer Treatment and Research
- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- Glycosylation and Glycoproteins Research
- Endoplasmic Reticulum Stress and Disease
- Genetics, Bioinformatics, and Biomedical Research
- Melanoma and MAPK Pathways
- Marine Sponges and Natural Products
- Biochemical and Molecular Research
- Developmental Biology and Gene Regulation
- Microbial Natural Products and Biosynthesis
- Cancer, Hypoxia, and Metabolism
- Viral Infectious Diseases and Gene Expression in Insects
- Protein Kinase Regulation and GTPase Signaling
- Click Chemistry and Applications
- Cancer-related Molecular Pathways
- Asymmetric Synthesis and Catalysis
- Silk-based biomaterials and applications
Yale University
2015-2024
University of New Haven
2010-2023
Whitney Museum of American Art
2019-2022
Institut thématique Génétique, génomique et bioinformatique
2008-2021
Dana-Farber Cancer Institute
1992-2014
Center for Discovery
2012
Council of Science Editors
2009
Northwestern University
2009
University of Kentucky
2008
Institute of Molecular and Cell Biology
2006
The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One the best-characterized enzymes that catalyzes attachment ubiquitin to is a ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought artificially target protein SCF for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting molecule 1 (Protac-1),...
Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs), are thought to act at an integration point for multiple biochemical signals because they activated by a wide variety of signals, rapidly phosphorylated on threonine and tyrosine, highly conserved. A critical kinase lies upstream MAP stimulates the enzymatic activity kinase. The structure this kinase, denoted MEK1, M AP or E RK k inase, was elucidated from complementary DNA sequence shown be...
The proteasome regulates cellular processes as diverse cell cycle progression and NF-κB activation. In this study, we show that the potent antitumor natural product epoxomicin specifically targets proteasome. Utilizing biotinylated-epoxomicin a molecular probe, demonstrate covalently binds to LMP7, X, MECL1, Z catalytic subunits of Enzymatic analyses with purified bovine erythrocyte reveal potently inhibits primarily chymotrypsin-like activity. trypsin-like peptidyl-glutamyl peptide...
Significance We describe the development of a small molecule that mediates degradation bromodomain and extra-terminal (BET) proteins its application in treatment castration-resistant prostate cancer (CRPC). Few therapeutic options exist to treat CRPC, especially CRPC tumors expressing constitutively active androgen receptor (AR) splice variants lack ligand-binding domain can effect androgen-independent transactivation target genes. Importantly, we demonstrate targeted BET using...
The inhibition of new blood vessel formation (angiogenesis) is an effective means limiting both the size and metastasis solid tumors. leading anti-angiogenic compound, TNP-470, has proven to be in vitro animal model studies, currently being tested phase III antitumor clinical trials. Despite many detailed pharmacological little known molecular mode action TNP-470. Using a derivative TNP-470 parent fungal metabolite, fumagillin, we have purified mammalian protein that selectively covalently...
Abstract Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of challenges currently faced in modern drug development programs. PROTAC employs small molecules that recruit target proteins for ubiquitination and removal by proteasome. The synthesis compounds mediate degradation c‐ABL BCR‐ABL recruiting either Cereblon or Von Hippel Lindau E3 ligases reported. During course their development, we discovered...
E3 ubiquitin ligases, which bind protein targets, leading to their ubiquitination and subsequent degradation, are attractive drug targets due exquisite substrate specificity. However, the development of small-molecule inhibitors has proven extraordinarily challenging as modulation ligase activities requires targeting protein–protein interactions. Using rational design, we have generated first small molecule von Hippel–Lindau (VHL), recognition subunit an ligase, important target in cancer,...
Abstract PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related families remain elusive. Here, we generate isoform-selective p38 MAPK family using single warhead (foretinib) and recruited (von Hippel-Lindau)....
The fungal metabolite fumagillin suppresses the formation of new blood vessels, and a analog is currently in clinical trials as an anticancer agent. molecular target methionine aminopeptidase-2 (MetAP-2). A 1.8 resolution crystal structure free inhibited human MetAP-2 shows covalent bond formed between reactive epoxide histidine-231 active site MetAP-2. Extensive hydrophobic water-mediated polar interactions with other parts provide additional affinity. Fumagillin-based drugs inhibit but not...