A5014655667- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- RNA modifications and cancer
- Histone Deacetylase Inhibitors Research
- Chemical Reactions and Isotopes
- Cancer-related gene regulation
- RNA Interference and Gene Delivery
- Genomics and Chromatin Dynamics
- Chromatin Remodeling and Cancer
- Cancer Genomics and Diagnostics
- Hemoglobinopathies and Related Disorders
- Peptidase Inhibition and Analysis
- Cancer, Hypoxia, and Metabolism
- CRISPR and Genetic Engineering
- CAR-T cell therapy research
- FOXO transcription factor regulation
- Mechanisms of cancer metastasis
- Cellular transport and secretion
- Melanoma and MAPK Pathways
- Chemokine receptors and signaling
- RNA regulation and disease
- Endoplasmic Reticulum Stress and Disease
- Advanced biosensing and bioanalysis techniques
Harvard University
2012-2024
Dana-Farber Cancer Institute
2015-2024
Novartis (United States)
2018-2024
Novartis (Switzerland)
2019
Novartis Institutes for BioMedical Research
2019
Boston University
2017
Dana-Farber Brigham Cancer Center
2017
Brigham and Women's Hospital
2017
Broad Institute
2014-2016
University of Michigan–Ann Arbor
2014
A degrading game plan for cancer therapy Certain classes of proteins that contribute to development are challenging target therapeutically. Winter et al. devised a chemical strategy that, in principle, permits the selective degradation any protein interest. The involves chemically attaching ligand known bind desired another molecule hijacks an enzyme whose function is direct cell's machinery. In proof-of-concept study, they demonstrated transcriptional coactivator called...
The discovery of cancer dependencies has the potential to inform therapeutic strategies and identify putative drug targets. Integrating data from comprehensive genomic profiling cell lines functional characterization dependencies, we discovered that loss enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) its binding partner WDR77. MTAP is frequently lost due proximity commonly deleted tumor suppressor gene, CDKN2A....
The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite development chemical probes targeting BRD9 bromodomain, there is limited understanding function beyond acetyl-lysine recognition. We have therefore created first BRD9-directed degraders, through iterative design and testing heterobifunctional ligands that bridge bromodomain cereblon E3 ubiquitin ligase complex....
Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate complications and has been intently pursued. However, safe effective small-molecule inducers HbF remain elusive. We report the discovery dWIZ-1 dWIZ-2, molecular glue degraders WIZ transcription factor that robustly induce erythroblasts. Phenotypic screening cereblon (CRBN)-biased chemical library revealed as...
Post-translational modifications of histones alter chromatin structure and play key roles in gene expression specification cell states. Small molecules that target chromatin-modifying enzymes selectively are useful as probes have promise therapeutics, although very few currently available. G9a (also named euchromatin histone methyltransferase 2 (EHMT2)) catalyzes methylation lysine 9 on H3 (H3K9), a modification linked to aberrant silencing tumor-suppressor genes, among others. Here, we...
Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including development a novel selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK knockout, chemical-induced protein degradation strategy, RNA interference CRISPR to validate as therapeutic in basal-like breast cancers (BBC). common culture conditions, found that small molecule...
Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated target. This particularly relevant for proteins depending on scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability multiple RTKs chemical by E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN), we synthesized series phthalimide degraders based promiscuous kinase inhibitors sunitinib and PHA665752. While...
Abstract As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing developmental gene networks. Overexpression is commonly observed in human epithelial cancers, such as non–small cell lung carcinoma (NSCLC), yet definitive demonstration malignant transformation by deregulated remains elusive. Here, we demonstrate causal role overexpression NSCLC with new genetically engineered mouse models adenocarcinoma. Deregulated silences normal...
Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable can be targeted by compounds degrade them. For example, thalidomide-like drugs (IMiDs) the critical multiple myeloma transcription factors IKZF1 and IKZF3 recruiting them to cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic...
Dysregulated H3K27 demethylase activity in pVHL-deficient cells increases dependence on the EZH1 methyltransferase.
Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but major challenge of this strategy lies in determining the intracellular target and mechanism action (MoA) for validated hits. Here, we show that BRD0476, novel suppressor pancreatic β-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) signal transducer activation transcription 1 (STAT1) signaling promote survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476...
Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal to identify compounds that overcome resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting binding site distinct from known Eg5 inhibitors, BRD9876...
The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite development chemical probes targeting BRD9 bromodomain, there is limited understanding function beyond acetyl-lysine recognition. We have therefore created first BRD9-directed degraders, through iterative design and testing heterobifunctional ligands that bridge bromodomain cereblon E3 ubiquitin ligase complex....