A5045621618- Protein Degradation and Inhibitors
- Glioma Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Neuroblastoma Research and Treatments
- Chromatin Remodeling and Cancer
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Genomics and Chromatin Dynamics
- Histone Deacetylase Inhibitors Research
- Protein purification and stability
- Cancer Mechanisms and Therapy
- CAR-T cell therapy research
- Renal and related cancers
- HIV Research and Treatment
- Acute Lymphoblastic Leukemia research
- Viral Infectious Diseases and Gene Expression in Insects
- Epigenetics and DNA Methylation
- Monoclonal and Polyclonal Antibodies Research
- Neonatal Respiratory Health Research
- Enzyme Structure and Function
- Advanced biosensing and bioanalysis techniques
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Chronic Lymphocytic Leukemia Research
- Cancer-related gene regulation
Dana-Farber Cancer Institute
2020-2024
University of California, San Diego
2024
Harvard University
2022
Abstract Gene expression is regulated by promoters and enhancers marked histone H3 lysine 27 acetylation (H3K27ac), which established the paralogous acetyltransferases (HAT) EP300 CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized cancer cells. We demonstrate that majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. controls enhancer interacting with TFAP2β, transcription factor member...
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...
The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting extraterminal domain (BET) proteins into non-BET bromodomains. two most relevant oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our reactions enabled...
Abstract Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index....
As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors are currently re-entering stage cancer treatments. Therefore, we developed 3D volumetric clearing-assisted tissue click chemistry (vCATCH) image in vivo target-bound drugs by leveraging unique kinetics reactions. In mice, vCATCH...
Epigenetic reprogramming to pluripotency requires extensive remodeling of chromatin landscapes silence existing cell-type-specific genes and activate genes. ATP-dependent complexes are important regulators structure gene expression; however, the role recently identified Bromodomain-containing protein 9 (BRD9) associated non-canonical BRG1-associated factors (ncBAF) complex in remains unknown. Here, we show that genetic or chemical inhibition BRD9, as well ncBAF subunit GLTSCR1, but not...
Abstract Bifunctional molecules such as targeted protein degraders induce proximity to promote gain-of-function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading an intensive focus on strategies that can accelerate their identification optimization. We others previously used chemical proteomics map degradable target space, these datasets been develop train multiparameter models extend degradability predictions...
Abstract Based on a previously reported 1,4‐dihydropyridinebutyrolactone virtual screening hit, nine lactone ring‐opened ester and seven amide analogs were prepared. The designed to provide interactions with residues at the entrance of ZA loop testis‐specific bromodomain (ZA) channel enhance affinity selectivity for extra‐terminal (BET) subfamily bromodomains. Compound testing by AlphaScreen showed that neither nor lactam was improved BRD4‐1 first (BRDT‐1). esters retained comparable parent...
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 Oncofetal transcription factor SALL4 is essential for cancer cell survival. 1-5 Recently, several groups reported that immunomodulatory imide drugs (IMiDs) could degrade in a proteasome-dependent manner. 6,7 Intriguingly, we observed IMiDs had no effect on SALL4-positive cells. Further studies demonstrated only SALL4A, one of the isoforms. This finding raises possibility SALL4B, isoform not affected by IMiDs, may be SALL4-mediated SALL4B knockdown led to an increase apoptosis and...
Bifunctional molecules such as targeted protein degraders induce proximity to promote gain‐of‐function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading an intensive focus on strategies that can accelerate their identification optimization. We others previously used chemical proteomics map degradable target space, these datasets been develop train multiparameter models extend degradability predictions proteome. In this...
Bifunctional molecules such as targeted protein degraders induce proximity to promote gain‐of‐function pharmacology. These powerful approaches have gained broad traction across academia and the pharmaceutical industry, leading an intensive focus on strategies that can accelerate their identification optimization. We others previously used chemical proteomics map degradable target space, these datasets been develop train multiparameter models extend degradability predictions proteome. In this...
Abstract Inhibitors of Bromodomain and Extra Terminal (BET) proteins are investigated for various therapeutic indications, but selectivity BRD2, BRD3, BRD4, BRDT their respective tandem bromodomains BD1 BD2 remains suboptimal. Here we report selectivity‐focused structural modifications previously reported dihydropyridine lactam 6 by changing linker length type the side chain in efforts to engage unique arginine 54 (R54) residue BRDT‐BD1 achieve BRDT‐selective affinity. We found that analogs...
Abstract Epigenetic reprogramming requires extensive remodeling of chromatin landscapes to silence cell-type specific gene expression programs. ATP-dependent chromatin-remodeling complexes are important regulators structure and expression; however, the role Bromodomain-containing protein 9 (BRD9) associated ncBAF (non-canonical BRG1-associated factors) complex in remains unknown. Here, we show that genetic suppression BRD9 as well subunit GLTSCR1, but not closely related BRD7, increase...
<div>Abstract<p>Gene expression is regulated by promoters and enhancers marked histone H3 lysine 27 acetylation (H3K27ac), which established the paralogous acetyltransferases (HAT) EP300 CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized cancer cells. We demonstrate that majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. controls enhancer interacting with TFAP2β, transcription...
<div>Abstract<p>Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that refractory to standard-of-care therapeutic modalities. The primary genetic drivers a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting an aberrant epigenetic landscape. To interrogate for dependencies, we performed CRISPR screen and show...
<div>Abstract<p>Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that refractory to standard-of-care therapeutic modalities. The primary genetic drivers a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting an aberrant epigenetic landscape. To interrogate for dependencies, we performed CRISPR screen and show...