A5061258831- Chemical Synthesis and Analysis
- Heat shock proteins research
- Computational Drug Discovery Methods
- Lung Cancer Treatments and Mutations
- Rare-earth and actinide compounds
- Click Chemistry and Applications
- Colorectal Cancer Treatments and Studies
- Microtubule and mitosis dynamics
- Cancer Treatment and Pharmacology
- Monoclonal and Polyclonal Antibodies Research
- RNA and protein synthesis mechanisms
- HER2/EGFR in Cancer Research
- Biochemical effects in animals
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- PARP inhibition in cancer therapy
- Protein Structure and Dynamics
- ATP Synthase and ATPases Research
- Cancer therapeutics and mechanisms
- Synthesis and Biological Evaluation
- Cancer-related Molecular Pathways
- Melanoma and MAPK Pathways
- Chemical Synthesis and Reactions
- Physics of Superconductivity and Magnetism
- HIV Research and Treatment
Nerviano Medical Sciences
2012-2022
ETH Zurich
1984-2005
Novartis (Switzerland)
1990-2001
Los Alamos National Laboratory
1999
Board of the Swiss Federal Institutes of Technology
1985-1995
University of California, San Diego
1989-1992
City of Hope
1987
Beckman Research Institute
1987
Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the spectrum 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration phosphoproteomic...
Abstract Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non–small cell lung cancers (NSCLC) as well other tumor types their oncogenic relevance actionable targets has been demonstrated by the efficacy selective kinase inhibitors such crizotinib, ceritinib, alectinib. More recently, low-frequency rearrangements TRK kinases have described NSCLC, colorectal carcinoma, glioblastoma, Spitzoid melanoma. Entrectinib, whose discovery...
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine responsible for the development of different tumor types. Despite remarkable clinical activity crizotinib (Xalkori), first ALK inhibitor approved in 2011, emergence resistance mutations and brain metastases frequently causes relapse patients. Within our drug discovery program, we identified compound 1, novel 3-aminoindazole active on biochemical cellular assays. Its optimization led to 2 (entrectinib), potent orally available...
One of the first steps in HIV gene expression is recruitment Tat protein to transcription machinery after its binding RNA response element TAR. Starting from a pool 3.2 × 10 6 individual chemical entities, we were able select hybrid peptoid/peptide oligomer 9 residues (CGP64222) that was block formation Tat/TAR complex vitro at nanomolar concentrations. NMR studies demonstrated compound binds similarly polypeptides derived and induces conformational change TAR Tat-binding site. In addition,...
Measurements of the electrical resistivity, magnetoresistance, ac and dc magnetic susceptibility specific heat on YbBiPt indicate this compound to be a IveryP heavy-electron system. The low-temperature Sommerfeld coefficient 8 J/${\mathrm{K}}^{2}$ (mole Yb) is not affected by phase transition at 0.4 K. We suggest that heavy-mass state in unconventional it develops from Bloch states an electronic subsystem with low carrier concentration.
The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. was originally isolated from a colorectal carcinoma (CRC) sample as component of somatic rearrangement (TPM3-NTRK1) resulting in expression oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding relevance this oncogene CRC. KM12 human CRC cell line expresses TPM3-TRKA and is hypersensitive to TRKA inhibition. We detailed characterization TPM3-NTRK1...
The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA is prominent target oncology, as testified by number candidates clinical testing that unselectively both PARP-1 its closest isoform PARP-2. goal our program was to find selective inhibitor would potentially mitigate toxicities arising from cross-inhibition Thus, an HTS campaign on proprietary Nerviano Medical Sciences (NMS) chemical collection, followed SAR optimization,...
Polo-like kinase 1 (PLK1) is a serine/threonine protein considered to be the master player of cell-cycle regulation during mitosis. It indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 overexpressed variety human tumors its overexpression often correlates with poor prognosis. Although five different PLKs are described humans, depletion or inhibition activity sufficient induce arrest apoptosis cancer cell lines xenograft tumor...
The formation of a heavy-electron state in magnetically ordered material is established by measurements the low-temperature specific heat U${\mathrm{Cu}}_{5}$ and UAg${\mathrm{Cu}}_{4}$. In this undergoes continuous but hysteretic phase transition which removes parts Fermi surface with high density electronic states leads to resistivity increase almost an order magnitude.
The value of α,β-unsaturated ketones as key intermediates for the combinatorial assembly four different templates on solid phase, namely pyrimidines, dihydropyrimidinones, pyridines, and pyrazoles, was explored with individual syntheses variably substituted model compounds. Starting from aldehydes grafted polystyrene support, Wittig Claisen−Schmidt reaction conditions were adapted to efficiently prepare phase. Further derivatization form pyrimidines succeeded a number amidines. In...
Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD+ to modify substrate proteins via the attachment poly(ADP-ribose) chains. a well established target oncology, as testified by number marketed drugs (e.g., Lynparza, Rubraca, Zejula, Talzenna) used for treatment ovarian, breast, prostate tumors. Efforts investigating uncharted region previously identified isoindolinone carboxamide series delivered (S)-13...
A traceless solid-phase synthesis of oxazoles 4 via Robinson−Gabriel reaction solid-supported α-acylamino ketones 2 has been achieved. The requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and trifluoroacetic anhydride used as cyclodehydrating agent. solvent dramatic effect on latter reaction, which goes completion follows cyclative-type mechanism only when an ethereal is used. Different synthetic routes have investigated toward assembling...
Maternal embryonic leucine zipper kinase (MELK) is upregulated in several types of tumor, including breast, prostate, and brain tumors. Its expression generally associated with cell survival, proliferation, resistance to apoptosis. Therefore, the potential MELK inhibitors as therapeutic agents recently attracting considerable interest. Here we report first structures complex AMP-PNP nanomolar inhibitors. Our studies shed light on role UBA domain, provide a characterization active site,...
The strong influence of changes the chemical composition on formation a heavy-electron ground state is demonstrated in uranium intermetallic compounds crystallizing cubic ${\mathrm{AuBe}}_{5}$ structure. most spectacular effect large enhancement low-temperature electronic specific heat ${\mathrm{UPt}}_{5}$ when one Pt atom per formula unit replaced by Au. ${\mathrm{UAuPt}}_{4}$ may be superconductor.
Recent developments of second generation Hsp90 inhibitors suggested a potential for development this class molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due brain metastases, sometimes related insufficient drug concentrations within the brain. Our objective was identify and characterize novel inhibitor able cross blood-brain barrier (BBB).Here described detailed biochemical crystallographic characterization NMS-E973....
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCis/trans isomers in cyclic peptides without N-substituted amidesDale F. Mierke, Toshimasa Yamazaki, Odile E. Said-Nejad, Eduard R. Felder, and Murray GoodmanCite this: J. Am. Chem. Soc. 1989, 111, 17, 6847–6849Publication Date (Print):August 1, 1989Publication History Published online1 May 2002Published inissue 1 August 1989https://pubs.acs.org/doi/10.1021/ja00199a058https://doi.org/10.1021/ja00199a058research-articleACS PublicationsRequest reuse...
Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant belonging to the AAA ATPase family involved number of essential cellular functions, including ubiquitin–proteasome mediated degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression VCP has been detected many cancer types sometimes associated with poor prognosis. Furthermore, mutations are causative some neurodegenerative disorders. In this paper we report...