A5046475464- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Multiple Myeloma Research and Treatments
- Marriage and Sexual Relationships
- Phytochemical compounds biological activities
- Synthesis and biological activity
- Melanoma and MAPK Pathways
- Chemical Synthesis and Analysis
- Phase-change materials and chalcogenides
- Synthesis and Characterization of Heterocyclic Compounds
- Quinazolinone synthesis and applications
- Glass properties and applications
- Porphyrin and Phthalocyanine Chemistry
- Chronic Lymphocytic Leukemia Research
- Molecular Junctions and Nanostructures
- Material Dynamics and Properties
- Crystallization and Solubility Studies
- Nuclear Receptors and Signaling
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- Pneumocystis jirovecii pneumonia detection and treatment
- Liver physiology and pathology
- Macrophage Migration Inhibitory Factor
- Pneumonia and Respiratory Infections
Florida State University
2024
AdventHealth Orlando
2024
Center for Global Development
2024
Novartis (United States)
2013-2024
University of Cincinnati
2020-2023
Novartis (China)
2023
Senckenberg Research Institute and Natural History Museum Frankfurt/M
2018
Novartis (Switzerland)
2011-2015
Novartis Institutes for BioMedical Research
2011-2014
Pathways Behavioral Services
2014
Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a selectivity profile. The key achieve these objectives was couple structure-based design approach intensive pharmacologic evaluation selected compounds during medicinal chemistry optimization process. Here, report on biologic characterization 2-morpholino pyrimidine derivative pan-PI3K...
Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety human cancers. Herein we describe structure guided optimization series 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where pharmacokinetic properties were improved by modulating electronics 6-position heterocycle, and overall druglike fine-tuned further modification 4-position substituent. The resulting 2,4-bismorpholino potent class I PI3K...
Abstract Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able drive progression of hematologic cancers. Consistent this, we found that PIMs are highly expressed human cancers and show isoform has a distinct expression pattern among disease subtypes. This suggests inhibitors all three would be effective treating multiple malignancies. Experimental Design: Pan-PIM proven difficult develop because PIM2 low Km for ATP and, thus, requires very...
Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans assess whether pan PIM inhibition may provide benefit cancer patients. Herein, the synthesis, vitro activity, vivo activity an acute myeloid xenograft model, preclinical profile potent selective inhibitor compound 8 (PIM447) are described. Starting from reported aminopiperidyl 3, a strategy improve microsomal stability was pursued resulting identification...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnantioselective Recognition by a New Chiral Stationary Phase at the Receptor LevelFrancesco Gasparrini, Domenico Misiti, Claudio Villani, Allen Borchardt, Matthew T. Burger, and W. Clark StillCite this: J. Org. Chem. 1995, 60, 14, 4314–4315Publication Date (Print):July 1, 1995Publication History Published online1 May 2002Published inissue 1 July 1995https://pubs.acs.org/doi/10.1021/jo00119a003https://doi.org/10.1021/jo00119a003research-articleACS...
Proviral insertion of Moloney virus (PIM) 1, 2, and 3 kinases are serine/threonine that normally function in survival proliferation hematopoietic cells. As high expression PIM1, is frequently observed many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, myeloid leukemias, there interest determining whether selective PIM inhibition can improve outcomes these cancers. Herein, we describe our efforts toward this goal. The structure guided optimization a singleton...
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase KRAS mutant tumors has established genetically engineered mouse models and tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective cellular potent inhibitors remain challenging identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as their preparation . WO 2014151616, 2014...
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due the complex nature RAF signaling, downstream activated RAS, poor overall kinase selectivity putative inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C inhibitor, which was developed by focusing on drug-like properties selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; J. Med. Chem.2017, 60,...
Abstract Features intrinsic to disorder and network aspects are ubiquitous in structural glasses. Among this important class of materials, chalcogenide glasses special—they built short‐range covalent forces, making them simpler than silicate that possess mixed ionic forces. Selenium‐based also display complex elastic phase transitions have been described from various models, including mean‐field approaches molecular simulations. These point the presence two sharply defined transitions, a...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthetic Ionophores. Encoded Combinatorial Libraries of Cyclen-based Receptors for Cu2+ and Co2+Matthew T. Burger W. Clark StillCite this: J. Org. Chem. 1995, 60, 23, 7382–7383Publication Date (Print):November 1, 1995Publication History Published online1 May 2002Published inissue 1 November 1995https://pubs.acs.org/doi/10.1021/jo00128a002https://doi.org/10.1021/jo00128a002research-articleACS PublicationsRequest reuse permissionsArticle...
Antibody–drug conjugates (ADCs) are an established modality that allow for targeted delivery of a potent molecule, or payload, to desired site action. ADCs, wherein the payload is protein degrader, emerging area in field. Herein we describe our efforts delivering Bruton's tyrosine kinase (BTK) bifunctional degrader 1 via CD79b mAb (monoclonal antibody) where linked at ligase binding portion cleavable linker mAb. The resulting 3 and 4, exhibit vitro degradation cytotoxicity comparable with 1,...
Adenomyoepithelioma (AME) of the breast is a rare tumor that can be benign or malignant and has varied morphological features. We report case 62-year-old female with history right cancer who presented abnormal screening mammography. The detection, presentation, imaging characteristics AMEs are discussed. nonspecific histologic appearance AME highlighted, emphasizing need for representative biopsy samples histopathological review diagnosis. Our underlines importance wide surgical excision...
Abstract The PI3K/Akt/mTor signaling pathway plays an important role in controlling cell growth, proliferation and survival. Through various mechanisms, the is frequently dysregulated human cancers, suggesting use of PI3K inhibitors as novel targeted anticancer therapeutic agents. To this end, substantial drug discovery efforts have been devoted both pharmaceutical companies academia to identify develop agents able specifically down regulate or other components tumors cells. Following...
Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety human cancers. A series 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors PI3Ks. Herein, we describe structure-guided optimization these with focus on replacing phenol moiety, while maintaining target inhibition and improving vivo properties. 6-heterocyclic pyrimidines, which potently inhibit PI3K, were...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFree Energy Calculations in Molecular Design: Predictions by Theory and Reality Experiment with Enantioselective Podand IonophoresMatthew T. Burger, Alan Armstrong, Frank Guarnieri, D. Quentin McDonald, W. Clark StillCite this: J. Am. Chem. Soc. 1994, 116, 8, 3593–3594Publication Date (Print):April 1, 1994Publication History Published online1 May 2002Published inissue 1 April...
A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and vivo potency against key respiratory pathogens. The modification involves replacing the natural methyl group core with a via chemical synthesis. From macrolide core, ketolides was prepared. Several compounds were found to be potent macrolide-sensitive -resistant bacteria. 6j 6k showed similar antimicrobial spectrum comparable activity commercial ketolide telithromycin. However,...
Abstract A substantial number of epidemiological and experimental studies support an important role for PI3K in the biology human cancer. The activation PI3K, its downstream effectors, has been clearly validated as essential step initiation maintenance tumorigenic phenotype. Parallel to clinical development our dual pan-PI3K/mTOR modulators (e.g., NVP-BEZ235), we continued drug discovery activities identify inhibitors with distinct biological pharmacological profiles. Following a...
Toll-like receptors (TLRs) are important sensors of the innate immune system that recognize conserved structural motifs and activate cells via a downstream signaling cascade. The CD180/MD1 molecular complex is an unusual member TLR family, since it lacks components normally required for signal transduction by other TLRs. Therefore CD180/MD 1 has been considered being incapable independently initiating cellular signals. Using chemogenetic approaches we identified specifically membrane bound...
Equimolar GexPxSe100–2x ternary glasses have been synthesized over a wide composition range, 4% < x 25%, and examined in Raman scattering, modulated DSC, volumetric experiments. Modulated DSC experiments show the enthalpy of relaxation at Tg to display square-well-like reversibility window with an onset (end) 9.0% (18.0%) respectively, thus, fixing rigidity transition, near xr = stress xs 18.0%. These findings that Intermediate-Phase (IP) resides 9% 18% range. Melt fragility index, m(x)...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTEnzymatic, Polymer-Supported Formation of an Analog the Trypsin Inhibitor A90720A: A Screening Strategy for Macrocyclic Peptidase InhibitorsMatthew T. Burger and Paul A. BartlettView Author Information Department Chemistry, University California Berkeley, 94720-1460 Cite this: J. Am. Chem. Soc. 1997, 119, 51, 12697–12698Publication Date (Web):December 24, 1997Publication History Received17 April 1997Published online24 December inissue 1...