A5027947663- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Fibroblast Growth Factor Research
- Chronic Myeloid Leukemia Treatments
- Kruppel-like factors research
- Epigenetics and DNA Methylation
- Chemical Synthesis and Analysis
- Biochemical and Molecular Research
- Chronic Lymphocytic Leukemia Research
- HER2/EGFR in Cancer Research
- Protein Kinase Regulation and GTPase Signaling
- Quinazolinone synthesis and applications
- Estrogen and related hormone effects
- Advanced Breast Cancer Therapies
- Eosinophilic Disorders and Syndromes
- Click Chemistry and Applications
- Hippo pathway signaling and YAP/TAZ
- Ubiquitin and proteasome pathways
- Synthesis and biological activity
- Lung Cancer Treatments and Mutations
- Protein Structure and Dynamics
- RNA modifications and cancer
- Cytokine Signaling Pathways and Interactions
- Cancer, Hypoxia, and Metabolism
- Angiogenesis and VEGF in Cancer
Novartis (Switzerland)
2015-2024
Novartis Institutes for BioMedical Research
2015-2024
Novartis (United States)
2001-2014
Novartis (Germany)
2011
Genomics Institute of the Novartis Research Foundation
2007
University of Basel
1997-2004
University of Copenhagen
2000
Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft these enzymes. In cellular settings using cell lines, this molecule able effectively specifically block dysfunctional activation...
Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy patients with FGFR2 fusion-positive ICC a phase II trial, but durability of response was limited some patients. Here, we report molecular basis for acquired resistance to three via integrative genomic characterization cell-free circulating tumor DNA (cfDNA), primary...
A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors the fibroblast growth factor receptor tyrosine kinases 1, 2, 3 by rationally designing substitution pattern aryl ring. On basis its in vitro profile, compound 1h (NVP-BGJ398) was selected for vivo evaluation showed significant antitumor activity RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support potential therapeutic use as a new anticancer agent.
Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Kα may have robust efficacy PIK3CA-mutant cancers while sparing patients side-effects associated with broader class I phosphoinositide 3-kinase (PI3K) family. Here, we report biologic properties 2-aminothiazole derivative NVP-BYL719, a inhibitor and its most common oncogenic mutant forms. The compound selectivity combined excellent drug-like translates to dose- time-dependent...
A systematic analysis reveals that out of 20 protein kinases examined, specific for either Ser/Thr or Tyr, the majority are extremely sensitive to staurosporine, with IC 50 values in low nanomolar range. few them however, notably CK1 and CK2, mitogen‐activated (MAP) kinase protein‐tyrosine CSK, relatively refractory staurosporine inhibition, exhibiting micromolar With all tested, namely PKA, CK1, MAP (ERK‐1), c‐Fgr, Lyn, CSK TPK‐IIB/p38 syk , inhibition was competitive respect ATP,...
Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, who have progressed to advanced-stage frequently fail respond or lose their response owing emergence of drug-resistant mutants protein. More than 40 such point mutations been observed in imatinib-resistant patients. The crystal...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTDiscovery of Potent Antagonists the Interaction between Human Double Minute 2 and Tumor Suppressor p53Carlos García-Echeverría, Patrick Chène, Marcel J. Blommers, Pascal FuretView Author Information Oncology Research Core Technologies, Novartis Pharma Inc., CH-4002 Basel, Switzerland Cite this: Med. Chem. 2000, 43, 17, 3205–3208Publication Date (Web):August 5, 2000Publication History Received8 December 1999Published online5 August 2000Published...
To assess the potential of protein kinase CK2 as a target for developing new antitumor agents, we have undertaken search inhibitors this enzyme. As part effort, report here discovery potent and selective inhibitor (5-oxo-5,6-dihydroindolo[1,2-a]quinazolin-7-yl)acetic acid. We identified novel structural type by high-throughput docking our corporate compound collection in ATP binding site homology model human CK2, using an appropriate protocol. The synthesis well that related analogues whose...
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough cause life-threatening disease. Vascular endothelial growth factor (VEGF) one the key promoters induced angiogenesis. VEGF receptors, tyrosine kinases Flt-1 and KDR, are expressed on vascular cells initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit KDR with IC(50) values < 0.1 microM....
In the course of random screening a pool CIBA chemicals, two pyrazolopyrimidines 1 and 2 have been identified as fairly potent inhibitors EGF-R tyrosine kinase. Using pharmacophore model for ATP-competitive interacting with active site protein kinase (PTK), class pyrazolo[3,4-d]pyrimidines was then optimized in an interactive process leading to series 4-(phenylamino)-1H-pyrazolo[3,4-d]-pyrimidines highly The most compounds 13, 14, 15, 17, 19, 22, 26, 28, 30 this inhibited PTK IC50 values...
As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as clinical candidate is currently phase 1 development. This article provides overview discovery this new inhibitor. The following aspects are addressed: mechanism action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic pharmacodynamic properties,...
Abstract Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and combination. Here, we describe the preclinical data of capmatinib, which supported biomarker strategy for rational patient selection. Experimental Design: selectivity cellular activity were assessed large screening panels. Antitumor efficacy was quantified set cell line– or patient-derived xenograft models, testing single-agent combination treatment depending...
The emergence of drug resistance is a primary concern in any cancer treatment, including with targeted kinase inhibitors as exemplified by the appearance Bcr-Abl point mutations chronic myeloid leukemia (CML) patients treated imatinib. In vitro approaches to identify have yielded mutation spectra that faithfully recapitulated clinical observations. To predict receptor tyrosine MET could emerge during inhibitor treatment patients, we conducted screen BaF3 TPR-MET cells using novel selective...
FGF19 signaling through the FGFR4/β-klotho receptor complex has been shown to be a key driver of growth and survival in subset hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted poorly conserved cysteine residue within ATP-binding site at position 552, two positions beyond gate-keeper residue. Several strategies for targeting this identify inhibitor starting points are summarized which made use both...
Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver and it third leading cause cancer-related deaths worldwide. Recently, aberrant signaling through FGF19/FGFR4 axis has been implicated in HCC. Here, we describe development FGF401, a highly potent selective, first class, reversible-covalent small-molecule inhibitor kinase activity FGFR4. FGF401 exquisitely selective for FGFR4 versus other FGFR paralogues FGFR1, FGFR2, FGFR3, all kinases kinome. excellent drug-like...
Abstract Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, abundance of protein does not correlate well with extent radiosensitivity across Given recent studies showing that temporal dynamics influence fate cultured cells in irradiation, we set out determine dynamic behavior and its impact on radiation vivo. We find radiosensitive tissues show prolonged signaling after radiation, while more resistant transient...
Abstract Mutations in the receptor tyrosine kinase FLT3 occur frequently patients with acute myeloid leukemia (AML) and lymphoblastic (ALL). Small molecules that selectively inhibit activity induce apoptosis blasts from AML mutations prolong survival animal models of FLT3-induced myeloproliferative disease. A spectrum structurally different small against have been described, their efficacy for treatment ALL is now being investigated clinical trials. Here, we describe results an vitro screen...