A5022807800- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Prostate Cancer Treatment and Research
- Ubiquitin and proteasome pathways
- Advanced biosensing and bioanalysis techniques
- Cancer-related Molecular Pathways
- Enzyme Production and Characterization
- Genomics and Chromatin Dynamics
- Protein Hydrolysis and Bioactive Peptides
- Chromatin Remodeling and Cancer
- Monoclonal and Polyclonal Antibodies Research
- Cancer Research and Treatments
- Phytase and its Applications
- Cell death mechanisms and regulation
- RNA Interference and Gene Delivery
Moffitt Cancer Center
2016-2022
University of South Florida
2016-2022
Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging DDB1-CUL4A-Roc1-RBX1 ubiquitin in human cells but not mouse cells, suggesting that sequence variations CRBN may cause its inactivation. Therapeutically, engagers have potential for broad applications cancer immune therapy specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine effects of...
Bromodomains regulate chromatin remodeling and gene transcription through recognition of acetylated lysines on histones other proteins. Bromodomain-containing protein TAF1, a subunit general factor TFIID, initiates preinitiation complex formation cellular transcription. TAF1 serves as cofactor for certain oncogenic factors is implicated in regulating the p53 tumor suppressor. Therefore, potential target to develop small molecule therapeutics diseases arising from dysregulated transcription,...
Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification mechanisms by which CRPCs evade deprivation therapies (ADT) critical develop novel therapeutics. We uncovered that rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, member BET bromodomain family, epigenetically promotes HOXB13 expression. Consistently, genetic disruption or...
Inhibition of the bromodomain containing protein 9 (BRD9) by small molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling complexes in cancer. However, reported BRD9 inhibitors also inhibit closely related bromodomain-containing 7 (BRD7), which has different biological functions. The structural basis for differential potency and selectivity largely unknown because lack information on BRD7. Here, we biochemically structurally characterized diverse with varying...
BRD4 and other members of the bromodomain extraterminal (BET) family proteins are promising epigenetic targets for development novel therapeutics. Among reported inhibitors dihydropteridinones benzopyrimidodiazepinones originally designed to target kinases PLK1, ERK5, LRRK2. While these kinase were identified as inhibitors, little is known about their binding potential structural details interaction with BET bromodomains. We comprehensively characterized a series newly dual BRD4-kinase...
Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription chromatin remodeling. BET family members BRD4 BRDT validated targets for cancer male contraceptive drug development, respectively. Due to the high structural similarity acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent may differ between BRDT, conferring an altered selectivity profile. Starting...
Selective inhibitors of bromodomain-containing protein 9 (BRD9) may have therapeutic potential in the treatment human malignancies and inflammatory diseases. A selective small molecule inhibitor that is well tolerated has proper pharmacokinetic properties required to explore function BRD9 BI-9564 (2) a cell permeable noncytotoxic provided scientific community biology determine its as drug target.
Several chemical probes have been developed for use in fluorescence polarization screening assays to aid drug discovery the bromodomain and extra-terminal domain (BET) proteins. However, few of those characterized literature. We designed, synthesized, thoroughly a novel pan-BET probe suitable high-throughput screening, structure–activity relationships, hit-to-lead potency selectivity identify characterize BET inhibitors.
<p>Supplementary Fig. 1. Epigenetic landscape and the transcription cofactor recruitment at HOXB13 enhancer region under various treatments; Supplementary Figure 2. BRD4 is a target of dual BET-kinase inhibitors in CRPCs; 3. Sensitivity normal AR negative cell lines to novel inhibitors; 4. but not FOXA1 epigenetic control prostate cancer cells; S5. Haploinsufficiency sensitizes CRPCs S6. AURKB expression correlates with human CTCs from mCRPC patients following Abiraterone therapy; S7....
<div>Abstract<p>Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification mechanisms by which CRPCs evade deprivation therapies (ADT) critical develop novel therapeutics. We uncovered that rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, member BET bromodomain family, epigenetically promotes HOXB13 expression....
<p>Supplementary Fig. 1. Epigenetic landscape and the transcription cofactor recruitment at HOXB13 enhancer region under various treatments; Supplementary Figure 2. BRD4 is a target of dual BET-kinase inhibitors in CRPCs; 3. Sensitivity normal AR negative cell lines to novel inhibitors; 4. but not FOXA1 epigenetic control prostate cancer cells; S5. Haploinsufficiency sensitizes CRPCs S6. AURKB expression correlates with human CTCs from mCRPC patients following Abiraterone therapy; S7....
<div>Abstract<p>Resistance to androgen receptor (AR) antagonists is a significant problem in the treatment of castration-resistant prostate cancers (CRPC). Identification mechanisms by which CRPCs evade deprivation therapies (ADT) critical develop novel therapeutics. We uncovered that rely on BRD4-HOXB13 epigenetic reprogramming for androgen-independent cell proliferation. Mechanistically, BRD4, member BET bromodomain family, epigenetically promotes HOXB13 expression....