Michael P. DeMartino
A5064099224- CRISPR and Genetic Engineering
- Renal and related cancers
- Animal Genetics and Reproduction
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- DNA Repair Mechanisms
- Asymmetric Synthesis and Catalysis
- Gastrointestinal motility and disorders
- RNA modifications and cancer
- Helicobacter pylori-related gastroenterology studies
- Congenital gastrointestinal and neural anomalies
- Oxidative Organic Chemistry Reactions
- Pharmacogenetics and Drug Metabolism
- Cancer-related gene regulation
- Fluorine in Organic Chemistry
- Computational Drug Discovery Methods
- Cell death mechanisms and regulation
- Chemical Synthesis and Analysis
- Digestive system and related health
- Pathogenesis and Treatment of Hiccups
- Metal-Catalyzed Oxygenation Mechanisms
- Statistical Methods in Clinical Trials
- Alkaloids: synthesis and pharmacology
- Traditional and Medicinal Uses of Annonaceae
- Quinazolinone synthesis and applications
South College
2010-2025
GlaxoSmithKline (United States)
2010-2024
Providence College
2024
WuXi AppTec (China)
2018
University of Oklahoma Health Sciences Center
2018
Columbia University
2018
Open Targets
2017
Scripps Research Institute
2006-2016
University of Delaware
2006
This full account presents the background on, discovery of, and extensive insight that has been gained into oxidative intermolecular coupling of two different carbonyl species. Optimization this process culminated in reliable scalable protocols for union amides, imides, ketones, oxindoles using soluble copper(II) or iron(III) salts as oxidants. Extensive mechanistic studies point to a metal-chelated single-electron-transfer case copper(II), while iron(III)-based couplings appear proceed...
No priming necessary: The intermolecular oxidative heterocoupling of imides and oxindoles to esters, ketones, lactones is shown for the first time be synthetically viable. Strategic use initial oxidation state reactants allows excision prefunctionalization steps (halogenation, enol-silane formation) concise synthesis unsymmetrical lignans, such as (−)-bursehernin (1). Oxidative dimerization enolates has been known since 19351 was studied further by Saegusa, Mislow, others in 1970s (Scheme 1...
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due expanded DNA (TA)n dinucleotide repeats. is a promising synthetic lethal target for MSI tumors, and inhibitors are in development. In this study, we used CRISPR-Cas9 base editing map residues critical cells, validating the domain as primary drug target. Fragment-based screening led development of potent highly selective covalent inhibitors. These compounds selectively suppressed model growth vitro...
While poor translatability of preclinical efficacy models can be responsible for clinical phase II failures, misdefinition the optimal PK properties required to achieve therapeutic also a contributing factor. In present work, pharmacological dependency end points in driving is demonstrated six common processes via model-based analysis. The analysis shows that response driven by multiple pharmacology-specific change with how defined. Moreover, results demonstrate most important chemical...
We report a ‘direct-to-biology’ (D2B) approach for optimising covalent acrylamide binders of protein targets and apply this to the identification selective cell-active inhibitor Werner (WRN) helicase. Inhibition WRN helicase activity exhibits synthetic lethal relationship with cancers displaying high microsatellite instability (MSI-H) is being pursued as therapeutic strategy in clinic. Using intact-protein liquid chromatography-mass spectrometry (LC-MS) screening, we identified fragment...
Ganz einfach: Erstmals gelang eine präparativ nützliche intermolekulare oxidative Heterokupplung von Imiden und Oxindolen an Ester, Ketone Lactone. Das strategisch geschickte Nutzen der ursprünglichen Oxidationsstufe Reaktanten ermöglicht den Verzicht auf Präfunktionalisierungsschritte (Halogenierung, Enolsilan-Bildung) erlaubt so rasche Synthese unsymmetrischer Lignane wie (−)-Bursehernin (1).
Abdominal pain and abnormal bowel habits represent major symptoms for irritable syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is completely understood, many functions gastrointestinal (GI) tract regulated by enteric nervous system (ENS). Inflammation or stress-induced expression growth factors cytokines may lead to hyperinnervation visceral afferent neurons in GI contribute pathophysiology IBS. Rearranged during transfection (RET) a neuronal factor...
RIP2 kinase was recently identified as a therapeutic target for variety of autoimmune diseases. We have reported previously selective 4-aminoquinoline-based inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling cellular models, rodent vivo human ex disease models. While this tool compound valuable validating the biological pathway, it suffered from activity at hERG ion channel poor PK/PD profile thereby limiting progression analog. Herein, we detail our...
A novel, one-step method for the synthesis of tri- and tetrasubstituted pyrimidin-4-ones is reported. This involves a titanium(IV)-mediated cyclization involving two sequential condensations primary β-ketoamides. The reaction operationally facile, readily scalable, offers rapid entry into differentially substituted pyrimidin-4-one scaffolds. high functional group compatibility allows substantial diversification in products generated from this transformation.
Many critical decisions faced in early discovery require a thorough understanding of the dynamic behavior pharmacological pathways following target engagement. From fundamental on optimal to pursue and ultimate drug product profile (combination modality, potency, compound properties) expected elicit desired clinical outcome tactical program such as what chemical series pursue, properties optimization, compounds synthesize progress, all demand detailed consideration pharmacodynamics....
The expression of RET in the developing enteric nervous system (ENS) suggests that may contribute to adult intestinal function. ENS cholinergic nerves play a critical role control colonic function through release acetylcholine (ACh). In current study, we hypothesized RET-mediated mechanism regulate ion transport and motility modulation nerves.The effect inhibition on active was assessed electrophysiologically rat tissue mounted Ussing chambers via measurements short circuit (Isc) upon...
Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress frequently associated development symptoms. Inflammation stress-induced expression growth factors cytokines may contribute pathophysiology IBS. Here, we aimed investigate therapeutic potential inhibiting receptor glial cell line-derived neurotrophic factor, rearranged...
An oxidative intermolecular enolate heterocoupling reaction was employed for the synthesis of <i>anti</i>-2,3-disubstituted succinic acid mono- and differentially protected diesters. Tactical approaches to access all diastereomers are discussed. The method applied a potent anticancer agent, BMS-906024.
Abstract Werner syndrome protein (WRN) is a RecQ-family helicase involved in the maintenance of genome integrity. Germline mutations WRN cause premature aging and cancer predisposition. Analysis systematic RNAi CRISPR screening data has previously revealed that essential for survival cell lines with high microsatellite instability (MSI-H). We have developed potent selective small-molecule inhibitors (WRNi) showed pharmacological inhibition causes lethality induction DNA damage markers...
The pregnane X receptor (PXR) regulates expression of proteins responsible for all three phases required the detoxification mechanism, which include CYP450 enzymes, phase II and multidrug efflux pumps. Therefore, PXR is a prominent that xenobiotic excretion drug-drug interactions. Pyrimidinone 1 an antagonist calcium sensing (CaSR) strong activator PXR. Repeat oral administration revealed diminished exposures over time, prohibited further progression. A medicinal chemistry campaign was...
<p>Supplementary Figure 1. Generating base editor-expressing MSI cell lines for screening. Supplementary 2. Quality control base-editor screens in lines. 3. Discovery and characterization of novel inhibitors WRN helicase. 4. Correlation inhibitor sensitivity with genetic molecular markers models. 5. Comparative analysis DNA damage MSS cells treated inactivation. 6: Effects GSK_WRN4 on colorectal cancer xenografts.</p>
<p>This table lists the results from Base editing screen</p>
<p>This file contains details of the BE sgRNA library</p>
<p>This file contain information on the Cell lines and organoids used in this study</p>
<div>Abstract<p>Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due expanded DNA (TA)<sub>n</sub> dinucleotide repeats. is a promising synthetic lethal target for MSI tumors, and inhibitors are in development. In this study, we used CRISPR–Cas9 base editing map residues critical cells, validating the domain as primary drug target. Fragment-based screening led development of potent highly selective covalent inhibitors. These...
<p>Supplementary Figure 1. Generating base editor-expressing MSI cell lines for screening. Supplementary 2. Quality control base-editor screens in lines. 3. Discovery and characterization of novel inhibitors WRN helicase. 4. Correlation inhibitor sensitivity with genetic molecular markers models. 5. Comparative analysis DNA damage MSS cells treated inactivation. 6: Effects GSK_WRN4 on colorectal cancer xenografts.</p>
<p>This file contain information on the Cell lines and organoids used in this study</p>
<p>This table lists the results from Base editing screen</p>
<p>This file contains details of the BE sgRNA library</p>