A5025867967- Protein Degradation and Inhibitors
- Synthetic Organic Chemistry Methods
- Chemical synthesis and alkaloids
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- PI3K/AKT/mTOR signaling in cancer
- Signaling Pathways in Disease
- Crystallography and molecular interactions
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Tuberous Sclerosis Complex Research
- Ubiquitin and proteasome pathways
- Bacterial biofilms and quorum sensing
- Catalytic C–H Functionalization Methods
- Alkaloids: synthesis and pharmacology
- Peptidase Inhibition and Analysis
- Polymer Surface Interaction Studies
- Chemical Synthesis and Reactions
- Advanced biosensing and bioanalysis techniques
- Synthesis and bioactivity of alkaloids
- Microbial Natural Products and Biosynthesis
- Mast cells and histamine
- Radical Photochemical Reactions
- Quinazolinone synthesis and applications
- Synthesis of β-Lactam Compounds
Novartis (China)
2024
Novartis (United States)
2023-2024
Novartis Institutes for BioMedical Research
2022
Novartis (Switzerland)
2022
Harvard University
2013
École Polytechnique Fédérale de Lausanne
2006-2010
Malignant tumors can evade destruction by the immune system attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, deficiency reduces tumor growth mice. Here we report discovery NVP-DKY709, selective molecular glue degrader that spares IKZF1/3. We describe recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 redirected degradation selectivity cereblon...
Direct C–H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because its application to pharmaceuticals, agrochemicals, and late-stage reactions on complex molecules. On the basis previous methods disclosed by our lab, we sought develop predictive model for site selectivity extend this aryl chemistry selected set heteroaromatic systems commonly used in pharmaceutical industry. Using electron density calculations, were able predict direct...
The hallmark of a molecular glue is its ability to induce cooperative protein–protein interactions, leading the formation ternary complex, despite weaker binding toward one or both individual proteins. Notably, extent cooperativity distinguishes glues from bifunctional compounds, which constitute second class inducers interactions. However, apart serendipitous discovery, there have been limited rational screening strategies for high exhibited by glues. Here, we propose binding-based screen...
The preparation of the polyketide natural products anguinomycin C and D is reported based on key steps such as Negishi stereoinversion cross coupling, Jacobsen Cr(III)-catalyzed Hetero Diels-Alder reaction, Evans B-mediated syn-aldol chemistry, B-alkyl Suzuki-Miyaura coupling. configuration both was established (5R,10R,16R,18S,19R,20S). Biological evaluation demonstrated that these are inhibitors nuclear export receptor CRM1, leading to shutdown CRM1-mediated protein at concentrations above...
The convergent synthesis of the polycyclic alkaloid (-)-nakadomarin A (1) is reported. plan identified macrocyclic lactam 4 as one important synthons (eight steps). other synthon (five steps) was bicyclo[6.3.0] 5 containing a single stereocenter that controlled all subsequent stereochemistry during assembly process. silyl triflate-promoted cascade and used to assemble bulk skeleton with exception C5-C6 bond. nakadomarin then completed in additional step.
The power of two! A natural product hybrid (see structure) composed a siderophore and an antibiotic separated by poly(ethylene glycol) linker enables the preparation antimicrobial cell-resistant surfaces simple dip-and-rinse procedure. anachelin (left) binds strongly to TiO2 surfaces, vancomycin is responsible for activity. Supporting information this article available on WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z801570_s.pdf or from author. Please note: publisher not content...
Abstract The synthesis and evaluation of new dopamine‐based catechol anchors coupled to poly(ethylene glycol) (PEG) for surface modification TiO 2 are reported. Dopamine is modified by dimethylamine–methylene ( 7 ) or trimethylammonium–methylene 8 groups, the preparation mPEG‐Glu didopamine polymer 11 presented. All these PEG polymers allow stable adlayers on be generated through mild dip‐and‐rinse procedures, as evaluated both variable angle spectroscopic ellipsometry X‐ray photoelectron...
Against nuclear export! Immunofluorescence assays indicate that anguinomycin C is a potent inhibitor of protein export from the nucleus. Key features in total synthesis this antitumor natural product include Cr-catalyzed enantioselective hetero-Diels–Alder reaction, Negishi reaction with stereoinversion, and application DIOZ auxiliary.
Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease overactivated mechanistic target rapamycin (mTOR) signaling, has demonstrated the therapeutic value mTOR inhibitors central nervous system (CNS) indications. Given that is an incomplete inhibitor function, we sought to develop new improved properties and suitable CNS disorders. Starting from in-house purine-based compound, optimization physicochemical thiazolopyrimidine...
Abstract Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting the elucidation of novel biological mechanisms. In parallel development DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient identify protein binders. Despite recent advancements this field, most DEL syntheses are limited by presence sensitive DNA-based constructs. Here, we describe design, synthesis, and...
The assembly of organometallic half-sandwich complexes with bis(dihydroxypyridine) ligands gives hexanuclear structures, which can be regarded as expanded triple-stranded helicates.
Abstract Molecular glues and bifunctional compounds that induce protein–protein associations provide a powerful general mechanism to modulate cell circuitry. We sought develop platform for the direct discovery of able association any two pre-selected proteins, using first bromodomain BRD4 VHL–elongin C–elongin B (VCB) complex as test system. Leveraging screening power DNA-encoded libraries (DELs), we synthesized ∼one million possess VHL-targeting fragment, variety connectors, diversity...
Die Kraft der Zwei! Der im Bild gezeigte Naturstoffhybrid aus einem Siderophor und Antibiotikum, die durch eine Polyethylenglycolbrücke verbunden sind, ermöglicht ein einfaches Eintauchverfahren Herstellung antimikrobieller zellresistenter Oberflächen. Anachelin-Siderophor (links) dient dabei starken Bindung an TiO2-Oberflächen, Vancomycin ergibt antimikrobielle Aktivität. Supporting information for this article is available on the WWW under...
Gegen Nuklearexport! Die Totalsynthese des antitumoralen Naturstoffs Anguinomycin C enthält als Schlüsselschritte eine Cr-katalysierte enantioselektive Hetero-Diels-Alder-Reaktion, Negishi-Reaktion unter Stereoinversion und die Anwendung DIOZ-Auxiliars. Laut Immunfluoreszenztests ist ein wirksamer Inhibitor Zellkernexports von Proteinen. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2007/z703134_s.pdf or from author. Please...
The hallmark of a molecular glue is its ability to induce cooperative protein-protein interactions, leading the formation ternary complex, despite weaker binding towards one or both individual proteins. Notably, extent cooperativity distinguishes glues from bifunctional compounds, second class inducers interactions. However, apart serendipitous discovery, there have been limited rational screening strategies for high exhibited by glues. Here, we propose binding-based screen DNA-barcoded...
ABSTRACT Molecular glues are small molecules that engage their target and presenter proteins cooperatively. FKBP12 molecular (FK506 rapamycin) were discovered several decades ago have been used clinically, but our understanding of the breadth targets has yet to be fully revealed. To identify novel glues, we constructed screened a multi-million- member non-macrocyclic FKBP12-ligand DNA-encoded library using 25 structurally distinct proteins. Synthesis validation selected hits in biophysical...
Abstract Objective Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal‐dominant pathogenic variants in either the TSC1 or TSC2 gene, and it characterized hamartomas multiple organs, such as skin, kidney, lung, brain. These changes can result epilepsy, learning disabilities, behavioral complications, among others. The mechanistic link between TSC target of rapamycin (mTOR) pathway well established, thus mTOR inhibitors potentially be used to treat clinical...
Synthetic studies towards the construction of cyclopenta[a]indene fragment heptacyclic marine metabolite sporolide are reported based on a hypothetical biosynthesis. The key step this biogenetic proposal includes Bergman cyclization an enediyne precursor. target synthetic study was prepared by Sonogashira cross-coupling two fragments, which cyclopentane from cyclopentenone, Morita-Baylis-Hillman reaction, and enantioselective Sharpless dihydroxylation.
Background: Everolimus, an allosteric mechanistic target of rapamycin (mTOR) inhibitor, recently demonstrated the therapeutic value mTOR inhibitors for Central Nervous System (CNS) indications driven by hyperactivation mTOR. A newer, potent brain-penetrant analog everolimus, referred to as (1) in this manuscript [(S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2-(thiazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)morpholine,(1)] catalytically inhibits function brain and increases lifespan mice with...
Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) small molecules has been pursued as ameliorate many complications but limited success. Herein, we report the discovery 10, novel, potent, and selective molecular glue degrader transcription factor WIZ that robustly induces HbF expression potential for SCD. 10 was optimized from phenotypic screening...