A5036149978- Microbial Natural Products and Biosynthesis
- Natural product bioactivities and synthesis
- Heat shock proteins research
- Cancer Treatment and Pharmacology
- Marine Sponges and Natural Products
- Toxin Mechanisms and Immunotoxins
- Computational Drug Discovery Methods
- Chromatin Remodeling and Cancer
- Fungal Infections and Studies
- Phytochemistry and Biological Activities
- Cancer Mechanisms and Therapy
- Bacillus and Francisella bacterial research
- interferon and immune responses
Foghorn Therapeutics (United States)
2025
University of Minnesota
2017-2022
Boston University
2019-2021
Innovative Design Labs (United States)
2017
BRM (SMARCA2) and BRG1 (SMARCA4) are mutually exclusive ATPase subunits of the mSWI/SNF (BAF) chromatin remodeling complex. BAF is an attractive therapeutic target because its role in transcription, mutations common cancer neurological disorders. Herein, we report discovery compound 1 (FHD-286) as a potent allosteric inhibitor dual from high-throughput screening hit with IC50 ∼27 μM. FHD-286 orally bioavailable antitumor activity mouse xenograft models uveal melanoma acute myeloid leukemia...
Abstract New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human under development as anticancer therapeutics, however, exert host toxicities that preclude their use antifungals. Seeking route species-selectivity, we investigate nucleotide-binding domain (NBD) from most common fungal pathogen,...
The molecular chaperone Hsp90, essential in all eukaryotes, plays a multifaceted role promoting survival, virulence, and drug resistance across diverse pathogenic fungal species. is also critically important, however, to the pathogen's human host, preventing use of known clinical Hsp90 inhibitors antifungal applications due concomitant host toxicity issues. With goal developing with acceptable therapeutic indices for treatment invasive infections, we initiated program design synthesize...
The essential eukaryotic chaperone Hsp90 regulates the form and function of diverse client proteins, many which govern thermotolerance, virulence, drug resistance in fungal species. However, use inhibitors as antifungal therapeutics has been precluded by human host toxicities suppression immune responses. We recently described resorcylate aminopyrazoles (RAPs) first class capable discriminating between (Cryptococcus neoformans, Candida albicans) isoforms biochemical assays. Here, we report...
Pironetin is a natural product with potent antiproliferative activity that forms covalent adduct α-tubulin via conjugate addition into the product's α,β-unsaturated lactone. Although pironetin's lactone involved in its binding to tubulin, structure-activity relationship at different positions of have not been thoroughly evaluated. For systematic evaluation relationships C4 and C5 pironetin, twelve analogues were prepared by total synthesis. Modifying stereochemistry and/or pironetin resulted...
Pironetin, the only crystallographically confirmed natural product to target α-tubulin, displays potent cytotoxic activity against sensitive and resistant A2780 ovarian cancer cell lines but is marginally active in vivo. We now report that pironetin has a short half-life (<7 min) human liver microsomes, suggesting its limited vivo efficacy due rapid metabolism. Further, we describe discovery of epoxypironetin as pironetin's major metabolite microsomes.