A5075891845- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Genomics and Chromatin Dynamics
- CAR-T cell therapy research
- Cancer Genomics and Diagnostics
- HIV Research and Treatment
- Endoplasmic Reticulum Stress and Disease
- Peroxisome Proliferator-Activated Receptors
- Cancer Mechanisms and Therapy
- HIV/AIDS drug development and treatment
- Click Chemistry and Applications
- Microtubule and mitosis dynamics
- Prostate Cancer Treatment and Research
- Chromatin Remodeling and Cancer
- Advanced biosensing and bioanalysis techniques
- RNA Interference and Gene Delivery
- RNA Research and Splicing
- Melanoma and MAPK Pathways
- DNA Repair Mechanisms
- RNA regulation and disease
- Immune cells in cancer
Novartis (United States)
2020-2024
Dana-Farber Cancer Institute
2015-2021
Harvard University
2014-2021
Broad Institute
2017-2021
Novartis (Switzerland)
2020
Novartis Institutes for BioMedical Research
2020
Boston University
2017
Yale University
2010-2015
Institut thématique Génétique, génomique et bioinformatique
2014
Center for Discovery
2012
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...
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,...
Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method inducing targeted involves use PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired interest. PROTACs have been successfully used degrade numerous proteins in cells, but peptidic ligase ligands previous hindered their into more mature probes or therapeutics. We report design novel class incorporate small molecule VHL HaloTag7 fusion...
By design: Novel small-molecule inhibitors of the interaction between von Hippel–Lindau ligase (VHL) and its molecular target HIF1α, a transcription factor involved in oxygen sensing, have been developed studied. The most potent inhibitor binds with an IC50 value 0.9 μM is thus first sub-micromolar VHL–HIF1α interaction. Detailed facts importance to specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available...
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....
Abstract Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity small molecule inhibitors. We describe dTAG V -1, an exclusively selective VHL-recruiting molecule, to rapidly degrade FKBP12 F36V -tagged proteins. -1 overcomes a limitation of previously reported CRBN-recruiting molecules recalcitrant oncogenes, supports combination degrader studies...
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...
Abstract Androgen receptor (AR)‐dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it the target several antitumor chemotherapeutic agents, including AR antagonist MDV3100/enzalutamide. Recent studies have shown that single mutation (F876L) converts MDV3100 action from an to agonist. Here we describe generation novel class selective androgen degraders (SARDs) address this resistance mechanism. Molecules containing hydrophobic degrons linked...
Significance Glioblastoma (GBM) cells develop intrinsic or acquired insensitiveness to BET bromodomain inhibitors (BBIs) yet persistent protein dependency. Selective degradation of proteins by a next-generation chemical compound undermines the dependency and exerts superior antineoplastic effects over inhibition bromodomain. Given significant difference between in GBM cells, chemically induced serves as promising strategy overcome anticipated clinical BBIs resistance.
Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation target oncoproteins and exhibit potent preclinical antitumor activity. To dissect mechanisms regulating tumor cell sensitivity different classes pharmacological "degraders" oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma resistance degraders targets (BET bromodomain proteins, CDK9) operating through CRBN (degronimids)...
Abstract The Von Hippel-Lindau Tumor Suppressor gene product (pVHL) is an E3 ligase substrate receptor that binds proline-hydroxylated HIF1-α, leading to its ubiquitin-dependent degradation. By using protein arrays, we identified a small molecule the HIF1-α binding pocket on pVHL and functions as molecular glue degrader of neosubstrate cysteine dioxygenase (CDO1) by recruiting it into VHL-cullin-ring complex selective CDO1 region involved in VHL recruitment was characterized through...
BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo inhibitors prompted need for structurally dissimilar ligands probes function. Using fluorous-tagged multicomponent reactions, we developed focused chemical library around 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis assessment allowed optimization novel based on an...