A5043798003- Cholesterol and Lipid Metabolism
- Signaling Pathways in Disease
- HIV Research and Treatment
- RNA and protein synthesis mechanisms
- interferon and immune responses
- Hormonal Regulation and Hypertension
- Protein Degradation and Inhibitors
- Biochemical and biochemical processes
- RNA Interference and Gene Delivery
- Steroid Chemistry and Biochemistry
- Nuclear Receptors and Signaling
- Ubiquitin and proteasome pathways
- Tea Polyphenols and Effects
- Synthesis of Indole Derivatives
- Peroxisome Proliferator-Activated Receptors
Broad Institute
2023
University of Oklahoma Health Sciences Center
2023
University of Oklahoma
2018-2023
Resistance development is an inevitable failure mode of many drugs, pointing to the need develop agents with orthogonal resistance mechanisms. Induced-proximity modalities, emergent class therapeutics, target protein-of-interest (POI) activity by forming a ternary complex and effector proteins, unlike classical inhibitors that form binary complexes. Using KRAS as model system, we employed base editor tiling mutagenesis screening show induced-proximity (e.g., molecular glues) exhibit...
Oxysterol-binding protein (OSBP) and OSBP-related 4 (ORP4) have emerged as potentially druggable targets in antiviral precision cancer drug development. Multiple structurally diverse small molecules function through targeting the OSBP/ORP family of proteins, including steroidal compounds OSW-1 T-00127-HEV2. Here, structure–activity relationships oxysterols related compound binding to human OSBP ORP4 are characterized. Oxysterols with hydroxylation at various side chain positions (i.e., C-20,...
Oxysterol-binding protein (OSBP) is a lipid transport and regulatory required for the replication of Enterovirus genus viruses, which includes many significant human pathogens. Short-term exposure (i.e., 1–6 h) to low dose 1 nM) natural product compound OSW-1 induces reduction cellular OSBP levels by ∼90% in multiple different cell lines with no measurable cytotoxicity, defect proliferation, or global proteome reduction. Interestingly, persists days after low-dose, transient treatment ended...
Abstract Aza‐substitution, the replacement of aromatic CH groups with nitrogen atoms, is an established medicinal chemistry strategy for increasing solubility, but current methods accessing functionalized azaindoles are limited. In this work, indole‐alkylating prenyltransferases (PTs) were explored as a to directly functionalize azaindole‐substituted analogs natural products. For this, series aza‐L‐tryptophans (Aza‐Trp) featuring N ‐substitution every position indole ring and their...