A5026694493- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- RNA and protein synthesis mechanisms
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- RNA Interference and Gene Delivery
- RNA Research and Splicing
- Peptidase Inhibition and Analysis
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- RNA modifications and cancer
- Multiple Myeloma Research and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Cellular Mechanics and Interactions
- Chromatin Remodeling and Cancer
- Polymer Surface Interaction Studies
- Microfluidic and Bio-sensing Technologies
- Lipid Membrane Structure and Behavior
- Supramolecular Self-Assembly in Materials
- Management Theory and Practice
- Force Microscopy Techniques and Applications
- HIV Research and Treatment
- Cancer Mechanisms and Therapy
- Epigenetics and DNA Methylation
Novartis (United States)
2019-2025
Novartis (China)
2024
Novartis (Switzerland)
2020-2022
Novartis Institutes for BioMedical Research
2020-2022
Novartis (Ireland)
2022
University of California, Berkeley
2020
Harvard University
2014-2017
Broad Institute
2017
Howard Hughes Medical Institute
2010-2017
University of California, San Francisco
2017
Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles converting protein-targeting ligands into degraders. To overcome this challenge, sought to identify transposable handle that would convert of their corresponding targets. Using the CDK4/6 inhibitor ribociclib prototype,...
Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific proteins in a proteasome-dependent manner. However, major limitation of TPD is the lack E3 ligase recruiters. Recently, we discovered natural product nimbolide covalent recruiter RNF114. Here, show broader utility an applications. We demonstrate that PROTAC linking to kinase BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades...
Interaction-dependent PCR (IDPCR) is a solution-phase method to identify binding partners from combined libraries of small-molecule ligands and targets in single experiment. Binding between DNA-linked induces formation an extendable duplex. Extension links codes that the ligand target into one selectively amplifiable DNA molecule. In model selection, IDPCR resulted enrichment encoding all five known protein−ligand pairs out 67 599 possible sequences.
Protein therapeutics are a blossoming industry, with revenues exceeding $51 billion in 2005 and growth rate nearly three times that of the overall pharmaceutical industry. Although it has been known for decades cationic polymers can transport molecular cargos across plasma membrane, inefficient cellular delivery continues to impede development protein drugs. Our lab recently reported small, folded proteins containing minimal motif embedded within type II polyproline (PPII) helix efficiently...
We describe the development and validation of interaction determination using unpurified proteins (IDUP), a method that selectively amplifies DNA sequences identifying ligand+target pairs from mixture DNA-linked small molecules protein targets in cell lysates. By operating lysates, IDUP preserves native post-translational modifications interactions with endogenous binding partners, thereby enabling study difficult-to-purify increasing potential biological relevance detected compared methods...
We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from mixture of DNA-linked small molecules and protein targets in cell lysates. In this study, we applied IDUP libraries DNA-encoded bioactive compounds DNA-tagged human kinases identify ligand:protein binding partners out 32 096 possible combinations single solution-phase library × experiment. The results recapitulated known...
There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types can be targeted inhibitors, we survey set electrophiles for their ability to label carboxylates. We functionalized an optimized ligand switch II pocket with previously reported react carboxylates characterized these compounds model nucleophiles Here, report aziridines stabilized diazo...
Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional sites compounds therapeutic development. However, the vast majority of ABPP methods covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report methionine-directed platform using Redox-Activated Chemical Tagging (ReACT), which leverages biomimetic oxidative ligation selective methionine modification. Application ReACT to oncoprotein...
Neural progenitor cells (NPCs) have shown promise in a number of models disease and injury, but for these to be safe effective, they must directed differentiate appropriately following transplantation. We developed photopolymerized hydrogel composed macromers poly(ethylene glycol) (PEG) bound poly(L-lysine) (PLL) that supports NPC survival directs differentiation. Green fluorescent protein (GFP) positive NPCs were encapsulated gels demonstrated up 17 days. When the at photoinitiator...
Splice modulating small molecules have been developed to promote the U1 snRNP engage with pre-mRNAs strong and altered sequence preference. Transcriptomic profiling of bulk RNA from compound treated cells enables detection RNAs impacted; however, it is difficult delineate whether transcriptional changes are a consequence direct treatment or trans-acting effects. To identify targets that bind directly splice compounds, we deployed photoaffinity labeling (PAL)-based Chem-CLIP approach. Through...
Abstract Targeted protein degradation is a powerful therapeutic modality that uses heterobifunctional small-molecules to induce proximity between E3 ubiquitin ligases and target proteins ubiquitinate degrade specific of interest. However, many are ubiquitinated degraded drive disease pathology; in these cases targeted stabilization (TPS), rather than degradation, the actively using small-molecule would be therapeutically beneficial. Here, we present Deubiquitinase-Targeting Chimera (DUBTAC)...
The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant SWI/SNF chromatin remodeling complexes. Loss function mutations in frequently observed various cancers, resulting a dependency on paralog for cancer cell proliferation. However, has never been targeted directly, high degree sequence similarity to poses challenge development selective binders. In this study, we used mRNA display identify peptidic ligands that bind with nanomolar affinities showed selectivity...
This paper argues that one of the board's main functions is to make decisions. In fact, quality and speed decision making key determinant board success or failure. The right decisions create wealth. One wrong can lose millions pounds. spite importance subject, most chairmen directors believe just something comes naturally. State-of-the-art knowledge technology, however, indicate it possible improve significantly timeliness making. For example, boards could deal with issues more effectively...
Abstract Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific targets in a proteasome-dependent manner. However, major limitation to broader TPD applications is the lack of E3 ligase recruiters. Recently, we discovered natural product nimbolide covalent ligand RNF114. When linked BET family inhibitor JQ1, resulting heterobifunctional PROTAC molecule was capable selectively BRD4 cancer cells....
Abstract Molecular glues are an intriguing therapeutic modality that harness small-molecules to induce interactions between proteins typically do not interact, thus enabling the creation of novel protein functions naturally encoded in biology. While molecular such as thalidomide and rapamycin have catalyzed drug discovery efforts, molecules rare often been discovered fortuitously, limiting their potential a general strategy for intervention disease. Historically, natural products proven be...
Splice modulating small molecules have been developed to promote the U1 snRNP engage with pre-mRNAs strong and altered sequence preference. Transcriptomic profiling of bulk RNA from compound treated cells enables detection RNAs impacted; however, it is difficult delineate whether transcriptional changes are a consequence direct treatment or trans-acting effects. To identify targets that bind directly splice compounds, we deployed photoaffinity labeling (PAL)-based Chem-CLIP approach. Through...
Activity-based protein profiling (ABPP) is a versatile strategy for enabling identification and characterization of new functional sites discovery lead compounds therapeutic development. Yet, the vast majority ABPP methods applied covalent drug target highly nucleophilic amino acids such as cysteine or lysine. Here, we report methionine-directed platform using Redox-Activated Chemical Tagging (ReACT), which leverages biomimetic oxidative ligation selective methionine modification....