A5080700945- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Cancer-related gene regulation
- RNA modifications and cancer
- Statistical Methods in Clinical Trials
- Epigenetics and DNA Methylation
- Metabolomics and Mass Spectrometry Studies
- Drug Transport and Resistance Mechanisms
- Analytical Chemistry and Chromatography
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immune cells in cancer
- Liver Disease Diagnosis and Treatment
- Structural Behavior of Reinforced Concrete
- Cancer, Hypoxia, and Metabolism
- Natural Antidiabetic Agents Studies
- Electrochemical Analysis and Applications
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Diabetes Treatment and Management
- RNA and protein synthesis mechanisms
- Quinazolinone synthesis and applications
University of Wisconsin–Madison
2024
Icahn School of Medicine at Mount Sinai
2020-2024
National Institutes of Health
2020-2023
The Graduate Center, CUNY
2022-2023
National Center for Advancing Translational Sciences
2019-2023
University of British Columbia
2016
City College of New York
2014
With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully advanced to clinics for treating cancer. However, pharmacologic activation of tumor-suppressor proteins cancer treatment remains a major challenge. Here, we present novel Acetylation Targeting Chimera (AceTAC) strategy acetylate the p53 tumor suppressor protein. We discovered and characterized first p53Y220C AceTAC, MS78, which...
A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via optimized linker. Several these were highly potent (IC50 < 10 nM) selective against PI3Kγ, δ HDAC6 enzymes exhibited good antiproliferative activity multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant FLT3-resistant AML lines primary blasts from patients,...
Abstract Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono‐ubiquitination (H2AK119ub). B cell‐specific Moloney murine leukemia virus Integration site (BMI1) and really interesting new gene 1B (RING1B) are PRC1 core components play critical roles in the development of various cancers. However, therapeutic agents targeting very limited. In this study, MS147, first degrader components, BMI1 RING1B, discovered via a novel...
Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- dimethylation of histone H3 9 (H3K9), have been implicated in numerous cancers. Recent studies uncovered both catalytic noncatalytic oncogenic functions G9a/GLP. As such, G9a/GLP inhibitors displayed limited anticancer activity. Here, we report the discovery first-in-class proteolysis targeting chimera (PROTAC) degrader 10 (MS8709), as a potential therapeutic. induces degradation concentration-, time-,...
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation reduced nicotinamide adenine dinucleotide as final step in glycolytic pathway. Glycolysis plays an important role metabolic plasticity cancer cells and has long been recognized a potential therapeutic target. Thus, potent, selective inhibitors LDH represent attractive approach. However, date, pharmacological agents have failed achieve significant target engagement vivo, possibly because...
Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity an E3 ubiquitin ligase. In this study, we discovered for first time cereblon (CRBN) can be employed bridged approach and report first-in-class CRBN-recruiting EED-binding polycomb repressive 1 (PRC1) degrader, compound
Efficiently circumventing the blood-brain barrier (BBB) poses a major hurdle in development of drugs that target central nervous system. Although there are several methods to determine BBB permeability small molecules, Parallel Artificial Membrane Permeability Assay (PAMPA) is one most common assays drug discovery due its robust and high-throughput nature. Drug long costly venture, thus, any advances streamline this process beneficial. In study, ∼2,000 compounds from over 60 NCATS projects...
Hepatic metabolic stability is a key pharmacokinetic parameter in drug discovery. Metabolic usually assessed microsomal fractions and only the best compounds progress discovery process. A high-throughput single time point substrate depletion assay rat liver microsomes (RLM) employed at National Center for Advancing Translational Sciences. Between 2012 2020, RLM data was generated ~ 24,000 from more than 250 projects that cover wide range of pharmacological targets cellular pathways. Although...
Previously, we reported a first-in-class von Hippel–Lindau (VHL)-recruiting mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) degrader, MS432. To date, only two MEK1/2 degrader papers have been published very limited structure–activity relationships (SAR) reported. Here, describe our extensive SAR studies exploring both (VHL) cereblon (CRBN) E3 ligase ligands variety of linkers, which resulted in novel, improved VHL-recruiting degraders, 24 (MS928) 27 (MS934), the first...
The well-known tumor suppressor p53 is mutated in approximately half of all cancers. Y220C mutation one the major hotspot mutations. Several small-molecule stabilizers p53Y220C have been developed. We recently developed a new technology for inducing targeted protein acetylation, termed acetylation targeting chimera (AceTAC), and first AceTAC that effectively acetylated at lysine 382. Here, we report structure-activity relationship (SAR) studies AceTACs, which led to discovery novel AceTAC, compound
Inappropriate use of prescription drugs is potentially more harmful in fetuses/neonates than adults. Cytochrome P450 (CYP) 3A subfamily undergoes developmental changes expression, such as a transition from CYP3A7 to CYP3A4 shortly after birth, which provides potential way distinguish medication effects on and The purpose this study was build first-in-class predictive models for both inhibitors substrates CYP3A7/CYP3A4 using chemical structure analysis. Three metrics were used evaluate model...
Lactate dehydrogenase (LDH) is a key glycolytic enzyme and biomarker of aggressive cancers. LDHA LDHB are two main LDH subunits, both frequently overexpressed in tumors essential for tumor growth. A number LDHA/B small-molecule inhibitors have been developed. Here, we report the discovery first proteolysis targeting chimera (PROTAC) degrader, compound 22 (MS6105). potently degraded time- ubiquitin-proteasome system-dependent manner. Using an unbiased global proteomic study, confirmed that...
The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of nucleolus. PNC enriched with RNA transcripts and RNA-binding proteins, reflecting different states genome organization. prevalence positively correlates cancer progression metastatic capacity, making it useful marker for progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce in cells. We identified further optimized pyrrolopyrimidine...
Objective Plasma apolipoprotein (apo)D, a ubiquitously expressed protein that binds small hydrophobic ligands, is found mainly on HDL particles. According to studies of human genetics and lipid disorders, plasma apoD levels positively correlate with HDL-cholesterol apoAI levels. Thus, we tested the hypothesis was regulator metabolism. Methods & Results We compared lipoprotein profiles wild-type (WT) C57BL/6 mice apoD−/− background after receiving high fat-high cholesterol diet for 12 weeks....
Cytochrome P450 (CYP) 3A7 is one of the major xenobiotic metabolizing enzymes in human embryonic, fetal, and newborn liver. CYP3A7 expression has also been observed a subset adult population, including pregnant women, as well various cancer patients. The characterization not extensive other CYPs, health authorities have yet to provide guidance towards DDI assessment. To identify potential CYP3A7-specific molecules, we used P450-Glo enzyme assay screen library ∼5,000 compounds, FDA-approved...
Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- di-methylation of histone H3 9 (H3K9), have been implicated in numerous cancers. Recent studies uncovered both catalytic non-catalytic oncogenic functions G9a/GLP. As such, G9a/GLP inhibitors displayed limited anticancer activity. Here, we report the discovery first-in-class proteolysis targeting chimera (PROTAC) degrader,
Abstract G9a and GLP are lysine methyltransferases that catalyze dimethylation of histone H3 9 (H3K9me2), a transcriptionally repressive mark. Aberrantly expressed G9a/GLP has been implicated in numerous cancers, including prostate, lung, leukemia. The oncogenic activity is attributed to both its catalytic non-catalytic functions, such as forming co-activator complexes with p300, CARM1, GRIP1, Mediator positively regulate gene transcription. As such, current enzymatic inhibitors display...
Pharmacological reactivation of the tumor suppressor p53 remains a key challenge for treatment cancer. Acetylation Targeting Chimera (AceTAC), novel technology is previously reported that hijacks lysine acetyltransferases p300/CBP to acetylate p53Y220C mutant. However, are only harnessed AceTAC development date. In this study, it demonstrated first time TAF1 acetyltransferase can be recruited p53Y220C. A TAF1-recruiting AceTAC, MS172 discovered, which effectively acetylates 382 in...
Abstract Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono-ubiquitination (H2AK119ub). BMI1 and RING1B are PRC1 core components play critical roles in the development of various cancers. However, therapeutic agents targeting very limited, small-molecule inhibitors displayed limited effectiveness killing cancer cells. In this study, MS147, first degrader components, RING1B, was discovered via a novel protein degradation...