A5025933204- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- CAR-T cell therapy research
- Sulfur-Based Synthesis Techniques
- Catalytic C–H Functionalization Methods
- Multiple Myeloma Research and Treatments
- Melanoma and MAPK Pathways
- Neuroscience and Neuropharmacology Research
- Protein Kinase Regulation and GTPase Signaling
- Synthesis and Catalytic Reactions
- Cell Adhesion Molecules Research
- Signaling Pathways in Disease
- Chromatography in Natural Products
- HER2/EGFR in Cancer Research
- Cyclopropane Reaction Mechanisms
- Fluorine in Organic Chemistry
- Chemical Synthesis and Reactions
- Microtubule and mitosis dynamics
- Organic and Inorganic Chemical Reactions
Dana-Farber Cancer Institute
2020-2024
Blueprint Medicines (United States)
2022
Harvard University
2020
Indiana University Bloomington
2016-2019
Indiana University
2017
This communication describes a mild, amide-directed fluorination of benzylic, allylic, and unactivated C-H bonds mediated by iron. Upon exposure to catalytic amount iron(II) triflate (Fe(OTf)2), N-fluoro-2-methylbenzamides undergo chemoselective fluorine transfer provide the corresponding fluorides in high yield. The reaction demonstrates broad substrate scope functional group tolerance without use any noble metal additives. Mechanistic computational experiments suggest that proceeds through...
Abstract Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics 1-3 . Molecular glues particular interest given their favorable size and chemical properties represent the only clinically approved degrader drugs 4-6 The discovery development molecular for novel targets, however, remains challenging. Covalent strategies could in principle facilitate glue by stabilizing neo-protein...
Abstract Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a trans -labeling covalent glue mechanism, termed ‘template-assisted modification’. We identified new series of BRD4 degraders recruit CUL4 DCAF16 ligase the second bromodomain (BRD4 BD2 ). Through...
Small molecules that can induce protein degradation by inducing proximity between a desired target and an E3 ligase have the potential to greatly expand number of proteins be manipulated pharmacologically. Current strategies for targeted are mostly limited in their scope with preexisting ligands. Alternate modalities such as molecular glues, exemplified glutarimide class ligands CUL4
Dysregulation of microtubules and tubulin homeostasis has been linked to developmental disorders, neurodegenerative diseases, cancer. In general, both microtubule-stabilizing destabilizing agents have powerful tools for studies microtubule cytoskeleton as clinical in oncology. However, many cancers develop resistance these agents, limiting their utility. We sought address this by developing a different kind agent: tubulin-targeted small molecule degraders. Degraders (also known...
Overexpression of PAK1, a druggable kinase, is common in several malignancies, and inhibition PAK1 by small molecules has been shown to impede the growth survival such cells. Potent inhibitors PAKs 1-3 have described, but clinical development hindered recent findings that PAK2 function required for normal cardiovascular adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides potential path forward, modest potency. Here, we report BJG-05-039, degrader consisting...
Substoichiometric iron mediates the thioetherification of unactivated aliphatic C–H bonds directed by resident silylperoxides. Upon exposure to a catalytic amount iron(II) triflate, TIPS-protected peroxides bearing primary, secondary, and tertiary sites undergo chemoselective remote with diaryl disulfides. The reaction demonstrates broad substrate scope functional group tolerance without use any noble metal additives. Mechanistic experiments suggest that proceeds through 1,5-H atom...
Focal adhesion kinase (FAK) is a tyrosine with prominent roles in protein scaffolding, migration, angiogenesis, and anchorage-independent cell survival an attractive target for the development of cancer therapeutics. However, current FAK inhibitors display dual inhibition and/or significant activity on several kinases. Although multitargeted at times therapeutically advantageous, such behavior can also lead to toxicity confound chemical-biology studies. We report novel series small molecules...
Abstract Molecular glue degraders have emerged as a powerful class of small-molecule therapeutics, demonstrated by the clinical successes thalidomide analogs in treatment hematological malignancies. These small molecules act recruiting ubiquitin ligases to disease-relevant proteins, resulting neosubstrate ubiquitination and degradation. To date, only number ligase - interactions been exploited molecular degraders, limiting targeting scope this therapeutic modality. Covalent chemistry, which...
Abstract Amplification and/or overexpression of the PAK1 gene is common in several malignancies, and inhibition by small molecules has been shown to impede growth survival such cells. Potent inhibitors its close relatives, PAK2, PAK3, have described, but clinical development hindered recent findings that PAK2 function required for normal cardiovascular adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, relatively modest potency Here, we...