A5000632520- Biochemical and Molecular Research
- Tuberculosis Research and Epidemiology
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Cellular transport and secretion
- Peptidase Inhibition and Analysis
- Cancer therapeutics and mechanisms
- Trypanosoma species research and implications
- Microbial Natural Products and Biosynthesis
- Multiple Myeloma Research and Treatments
- RNA and protein synthesis mechanisms
- Cell death mechanisms and regulation
- Chronic Myeloid Leukemia Treatments
- Enzyme Structure and Function
- Hemoglobin structure and function
- Protein Hydrolysis and Bioactive Peptides
- RNA Research and Splicing
- Photosynthetic Processes and Mechanisms
- Phytase and its Applications
- Cell Adhesion Molecules Research
- Cerebrospinal fluid and hydrocephalus
- HER2/EGFR in Cancer Research
- Histone Deacetylase Inhibitors Research
- Drug Transport and Resistance Mechanisms
- Silicon Effects in Agriculture
St. Jude Children's Research Hospital
2022-2025
Texas A&M University
2011-2021
Thalidomide and its analogues are frequently used in PROTAC design. However, they known to be inherently unstable, undergoing hydrolysis even commonly utilized cell culture media. We recently reported that phenyl glutarimide (PG)-based PROTACs displayed improved chemical stability and, consequently, protein degradation efficacy cellular potency. Our optimization efforts, aiming further improve the eliminate racemization-prone chiral center PG, led us development of dihydrouracil (PD)-based...
Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and target protein, resulting in the proteolysis. The discovery of molecular glue currently relies mostly on screening approaches. Here, we describe library cereblon (CRBN) ligands against panel patient-derived cancer cell lines, leading to SJ7095, potent degrader CK1α, IKZF1 IKZF3 proteins. Through structure-informed exploration structure activity relationship (SAR) around this molecule...
Abstract The spread of antibiotic resistance is a major challenge for the treatment Mycobacterium tuberculosis infections. In addition, efficacy drugs often limited by restricted permeability mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired this mechanism, we exploited β‐lactones as putative mycolic acid mimics block serine hydrolases involved in their biosynthesis. Among collection β‐lactones, found one hit with potent...
Abstract BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower threshold membrane We define trans as asymmetric “BH3-in-groove” triggering of dormant active BAK. mechanistically similar activation. The structure autoactivated BH3-BAK complex reveals conformational changes...
PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall vitro degradation antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor vivo pharmacokinetic profile. To further demonstrate PG...
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, agents should work through novel targets so that they are unencumbered by preexisting clinical to current treatments. Benzofuran 1 was identified as a potential lead TB inhibiting target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability inhibition hERG cardiac ion channel. This article describes...
The crystal structures of acyl carrier protein synthase (AcpS) from Mycobacterium tuberculosis (Mtb) and Corynebacterium ammoniagenes determined at pH 5.3 6.5, respectively, are reported. Comparison the Mtb apo-AcpS structure with recently reported AcpS-ADP complex revealed that AcpS adopts two different conformations: orthorhombic trigonal space-group show structural differences in α2 helix conformation α3-α4 connecting loop, which is a closed conformation. shows electron density for entire...
The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind cereblon (CRBN) alter its surface induce recruitment, ubiquitination, degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, CK1α). With the aim understanding modulating neosubstrate specificity, we recently reported discovery SJ3149 (
Yeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to between membranes in vitro, and stimulate phosphoinositide signaling vivo, does not exhibit these activities. Rather, a redox-active penta-coordinate high spin Fe III hemoprotein with heme-binding arrangement that involves co-axial tyrosine/histidine coordination strategy complex electronic structure connecting open shell iron d -orbitals...
In eukaryotes, calcium-binding proteins play a pivotal role in diverse cellular processes, and recent findings suggest similar roles for bacterial at different stages their life cycle. Here, we report the crystal structure of calcium dodecin, Rv0379, from Mycobacterium tuberculosis with dodecameric oligomeric assembly unique motif. Structure sequence analysis were used to identify orthologs Rv0379 ligand-binding specificity.
Abstract Eine der größten Herausforderungen für die Behandlung von Infektionen mit Mykobakterium tuberculosis ist Resistenzverbreitung. Des Weiteren Aktivität vieler Wirkstoffe durch limitierte Durchlässigkeit Mykomembran eingeschränkt. Etablierte Antibiotika setzen daher auf Lahmlegung Mykomembranbiosynthese und führen zu einem schnellen Sterben Zellen. Dieser Wirkmechanismus lieferte Motivation, β‐Lactone als mögliche Mykolsäuremimetika einzusetzen so Serinhydrolasen, in den Biosyntheseweg...
Abstract While the PROTAC approach to targeted protein degradation greatly benefits from rational design, discovery of molecular glue degraders currently relies on screening strategies. Here, we describe a library containing 3,630 cereblon binders against panel 9 patient-derived cancer cell lines. This led SJ7590, potent degrader CK1α, IKZF1 and IKZF3 proteins. Through structure-guided optimization strategy developed SJ3149, uniquely selective CK1α degrader. The crystal structure...
Abstract Yeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to between membranes in vitro, and stimulate phosphoinositide signaling vivo, does not exhibit these activities. Rather, a redox-active penta-coordinate high spin Fe III heme-binding with arrangement that involves co-axial tyrosine/histidine coordination strategy complex electronic structure connecting open shell iron d -orbitals three...