A5073010876- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Multiple Myeloma Research and Treatments
- Catalytic Cross-Coupling Reactions
- CAR-T cell therapy research
- Meat and Animal Product Quality
- Sulfur-Based Synthesis Techniques
- Aquaculture Nutrition and Growth
- Synthetic Organic Chemistry Methods
- N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
- Neuroblastoma Research and Treatments
- Peptidase Inhibition and Analysis
- Chemical Reactions and Isotopes
- Veterinary medicine and infectious diseases
- Chronic Lymphocytic Leukemia Research
- Antimicrobial Resistance in Staphylococcus
- Environmental Toxicology and Ecotoxicology
- Chronic Myeloid Leukemia Treatments
- RNA and protein synthesis mechanisms
- Parasites and Host Interactions
- Chemical synthesis and alkaloids
- Acute Myeloid Leukemia Research
- Lymphoma Diagnosis and Treatment
- Signaling Pathways in Disease
- Ammonia Synthesis and Nitrogen Reduction
St. Jude Children's Research Hospital
2017-2024
University of Southern California
2009-2022
Central South University
2012
Lafayette College
2004-2006
Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that and IMiD-based PROTACs rapidly hydrolyze commonly utilized cell media, which significantly affects their efficacy. We designed novel binders, phenyl glutarimide (PG)...
Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective identification efforts. Here, we describe synthesis, a large diverse library thalidomide analogues against panel patient-derived leukemia medulloblastoma cell lines. These efforts led potent novel GSPT1/2 displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, high oral bioavailability...
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...
A simple and efficient one-pot, three-component method has been developed for the synthesis of α-aminonitriles. This Strecker reaction is applicable aldehydes ketones with aliphatic or aromatic amines trimethylsilyl cyanide in presence a palladium Lewis acid catalyst dichloromethane solvent at room temperature.
Aberrant activation of the JAK-STAT signaling pathway has been implicated in pathogenesis a range hematological malignancies and autoimmune disorders. Here we describe design, synthesis, characterization JAK2/3 PROTACs utilizing phenyl glutarimide (PG) ligand as cereblon (CRBN) recruiter. SJ10542 displayed high selectivity over GSPT1 other members JAK family potency patient-derived ALL cells containing both JAK2 fusions CRLF2 rearrangements.
Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development modulators, however, has been largely limited to direct targeting catalytic active site conserved across multiple members an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group enzymes depends on interaction with Myocyte Enhancer Factor-2 (MEF2) their recruitment specific genomic...
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and there unmet need for targeted therapies, especially patients with relapsed disease. We have recently identified pre-T receptor lymphocyte-specific protein tyrosine kinase (LCK) signaling as a common therapeutic vulnerability in T-ALL. LCK inhibitor dasatinib showed efficacy against T-ALL preclinical studies T-ALL; however, this transient most cases. Leveraging the proteolysis targeting chimera (PROTAC)...
Despite significant advances over recent years, the treatment of T cell acute lymphoblastic leukemia (T-ALL) remains challenging. We have recently shown that a subset T-ALL cases exhibited constitutive activation lymphocyte-specific protein tyrosine kinase (LCK) and were consequently responsive to treatments with LCK inhibitors degraders such as dasatinib dasatinib-based PROTACs. Here we report design, synthesis in vitro/vivo evaluation SJ45566, potent orally bioavailable PROTAC.
Abstract Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis‐targeting chimera (PROTAC) approaches, owing to favorable drug‐like properties CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that and IMiD‐based PROTACs rapidly hydrolyze commonly utilized cell media, which significantly affects their efficacy. We designed novel binders, phenyl...
Methicillin-resistant Staphylococcus aureus (MRSA) strains that are resistant to all forms of penicillin have become an increasingly common and urgent problem threatening human health. They responsible for a wide variety infectious diseases ranging from minor skin abscesses life-threatening severe infections. The vra operon is conserved among S. encodes three-component signal transduction system (vraTSR) sensing responding cell wall stress. We developed novel multifaceted assay identify...
Profiling of the kinase-binding capabilities an aminopyrimidine analogue detected in a cellular screen St. Jude small-molecule collection led to identification novel series FMS-like tyrosine kinase 3 (FLT3) inhibitors. Structure-activity relationship studies development compounds exhibiting good potency against MV4-11 and MOLM13 acute myelogenous leukemia cells driven by FLT3, regardless their FLT3 mutation status. In vitro pharmacological profiling demonstrated that compound 5e shows...
The Heck coupling reactions of aryl halides and 3,4-dihydro-2H-pyran facilitated the regioselective synthesis arylated cyclic enol ethers. Good yields were obtained using 5 mol% an NHC-ligand-Pd-catalyst complex in presence K2CO3 DMF at 100 ˚C. use this catalytic system broadens substrate scope improves selectivity for cross-coupling process.
Abstract Separation of the sterols: cholesterol, cholestanol, β‐sitosterol, stigmasterol, ergosterol, campesterol, desmosterol, and brassicasterol was compared using reversed phase, multimodal, argentation thin layers. Layers tested include C18, C18W, NH2, CN, diol, C2, C8, phenyl bonded layers; hydrocarbon impregnated commercially prepared silica gel layers precoated with 10% silver nitrate. It determined that C18 acetonitrile–chloroform (40∶35) or petroleum ether–acetonitrile–methanol...
Abstract Under mild conditions, Pd(II) catalysts coordinated to tridentate NHC‐amidate‐ether ligand successfully activated the carbon‐hydrogen bond facilitate hydrogen/deuterium isotope exchange on methane. The structural features and catalytic behavior suggested an intriguing non‐redox system derived from amidate nitrogen. As nitrogen acts as internal base, metal center was able maintain oxidation state throughout reaction. Accordingly, demonstrated its reactivity stability during H/D...
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Influenza is one of the leading causes disease-related mortalities worldwide. Several strategies have been implemented during past decades to hinder replication cycle influenza viruses, all which resulted in emergence resistant virus strains. The most recent example baloxavir marboxil, where a single mutation active site target endonuclease domain RNA-dependent-RNA polymerase renders FDA approved compound ∼1000-fold less effective. Raltegravir first-in-class HIV inhibitor that shows modest...
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at glance that was extracted from about 200 leading journals. To access of an article which published elsewhere, please select “Full Text” option. The original trackable via the “References”
Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer, with a particularly dismal prognosis in patients relapsed diseases. Our group recently discovered LCK dependency as therapeutic vulnerability 33% of T-ALL and inhibitor dasatinib exhibited strong efficacy vitro vivo (Nat Cancer 2, 284, 2021). However, the transient inhibition by resulted only partial responses, novel agents are needed to suppress signaling sustained fashion achieve long-term efficacy. We...