A5009359386- Radiopharmaceutical Chemistry and Applications
- Cancer-related Molecular Pathways
- Prostate Cancer Treatment and Research
- Microtubule and mitosis dynamics
- Cancer Mechanisms and Therapy
- Advanced Breast Cancer Therapies
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Cancer, Lipids, and Metabolism
- Epigenetics and DNA Methylation
- Chronic Lymphocytic Leukemia Research
- Occupational and environmental lung diseases
- Monoclonal and Polyclonal Antibodies Research
- Mass Spectrometry Techniques and Applications
- Cancer Treatment and Pharmacology
- Fibroblast Growth Factor Research
- Peptidase Inhibition and Analysis
- Bone health and treatments
- Chemical Reactions and Isotopes
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
Bayer (Germany)
2015-2024
Ascendis Pharma (Denmark)
2023
Bayer (France)
2016
Pharmatest (Finland)
2013
University of Turku
2013
Bayer (United States)
2013
Fondazione IRCCS Istituto Nazionale dei Tumori
2012
University of Milan
2012
University of Chicago
1996-2001
Philipps University of Marburg
1991-1999
Because of the complexity derived from existence various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development PI3K inhibitors with pharmacologic pharmacokinetic profiles would allow best exploration different indications, combinations, dosing regimens. Here, we report BAY 80-6946, a highly selective potent pan-class I inhibitor sub-nanomolar IC50s against PI3Kα PI3Kδ. 80-6946 exhibited preferential inhibition (about 10-fold) AKT phosphorylation by...
The DNA damage response (DDR) secures the integrity of genome eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in by activating essential signaling pathways repair. Here, we studied effect novel selective ATR inhibitor BAY 1895344 tumor cell growth viability. Potent antiproliferative activity was demonstrated broad spectrum human lines....
CD4 + T cells can eliminate tumor in vivo the absence of CD8 cells. We have specific for a MHC class II-restricted, tumor-specific peptide derived from mutant ribosomal protein expressed by UV light-induced 6132A-PRO. By using neutralizing mAb murine IFN-γ and adoptive transfer into severe combined immunodeficient mice, we show that anti-IFN-γ treatment abolishes cell-mediated rejection . The were II negative, did not induce expression vitro Therefore, antigenic must be presented host Tumor...
Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It highly expressed tumor cells considered potential target for cancer therapy. Here, we report the discovery application novel potent small-molecule inhibitor mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL vitro addressed specificity within by studying Plk1 functions sister chromatid separation, centrosome maturation, spindle assembly. Moreover, used detailed...
Abstract Selective inhibition of exclusively transcription‐regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY‐958, optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited best overall profile vitro vivo, including high...
Abstract Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) bone metastases. This study examines mode-of-action and antitumor efficacy radium-223 in two xenograft models. Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12–17) based on lesion grade and/or serum PSA level administered (300 kBq/kg) vehicle, twice at...
Deregulated activity of cyclin-dependent kinases (CDK) results in loss cell-cycle checkpoint function and increased expression antiapoptotic proteins, which has been directly linked to the molecular pathology cancer. BAY 1000394 inhibits CDKs CDK1, CDK2, CDK3, CDK4, transcriptional CDK7 CDK9 with IC(50) values range between 5 25 nmol/L. Cell proliferation was inhibited at low nanomolar concentration a broad spectrum human cancer cell lines. In cell-based assays, inhibition phosphorylation...
Colon cancer is a heterogeneous tumor driven by subpopulation of stem cells (CSCs). To study CSCs in colon cancer, we used limiting dilution spheroid and serial xenotransplantation assays to functionally define the frequency panel patient-derived organoids. These studies demonstrated organoids be enriched for CSCs, which varied between tumors. Whole-transcriptome analysis identified WNT Hedgehog signaling components enhanced CSC-enriched tumors aldehyde dehydrogenase (ALDH)-positive CSCs....
Abstract Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha (TAT) has shown early signs activity in patients with refractory to beta radiation. We describe a novel, antibody-based TAT, the thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting alpha-particle emitter complexed by 3,2-HOPO chelator covalently linked fully human PSMA-targeting antibody. Experimental...
Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates assembly checkpoint (SAC) secure proper distribution of chromosomes daughter cells. Here, we report structure and functional characterization two novel selective Mps1 inhibitors, BAY 1161909 1217389, derived from structurally distinct chemical classes. 1217389 inhibited activity with IC50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both inhibitors...
Abstract Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment 3,2-HOPO chelator to an antibody enables specific complexation and delivery the particle emitter tumor cells. Because high energy short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in cell with limited damage surrounding tissue. We present herein preclinical evaluation mesothelin (MSLN)-targeted conjugate,...
Aberrant activation in fibroblast growth factor signaling has been implicated the development of various cancers, including squamous cell lung cancer, head and neck carcinoma, colorectal bladder cancer. Thus, receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated activity a pan-FGFR inhibitor, rogaratinib, biochemical, cellular vivo efficacy studies variety preclinical models. In vitro kinase assays demonstrate that rogaratinib potently selectively...
Prostate cancer is a frequent malignancy in older men and has very high 5‐year survival rate if diagnosed early. The prognosis much less promising the tumor already spread outside prostate gland. Targeted treatments mainly aim at blocking androgen receptor (AR) signaling initially show good efficacy. However, progression due to AR‐dependent AR‐independent mechanisms often observed after some time, novel treatment strategies are urgently needed. Dysregulation of PI3K/AKT/mTOR pathway advanced...
We show that serum-stimulated fibroblasts transiently express two different forms of fosB mRNA, which are generated by alternative splicing the transcript from a single gene. In addition to known long form (fosB-L), encoding protein 338 amino acids (FosB-L), second shorter (fosB-S) with deletion 140 bp was detected. This creates stop codon 3' leucine repeat, giving rise 237 (FosB-S) lacking carboxyl terminus FosB-L. Only FosB efficiently induces transformation in mouse and rat fibroblast...
The chicken anemia virus-derived protein Apoptin induces apoptosis specifically in human tumor and transformed cells not normal, untransformed cells. cell killing activity correlates with a predominantly nuclear localization of cells, whereas normal it is detected mainly cytoplasmic structures. To explore the role for Apoptin-induced death we employed mutagenesis strategy. First, demonstrated that C terminus contains bipartite-type signal. Strikingly, further investigation showed two...
BackgroundBone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis.
Darolutamide is a novel androgen receptor (AR) antagonist with distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers main metabolite keto‐darolutamide are strong, competitive wild type, also several mutants identified cancer patients which show reduced antagonism or even agonism. Darolutamide, two strong assays measuring N/C...
The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and chromosome congression, but role of its catalytic activity remains controversial. Here, we use two novel inhibitors, BAY-320 BAY-524, to demonstrate potent inhibition both vitro intact cells. Then, compared cellular phenotypes HeLa RPE1 cells with those protein depletion, indicative or scaffolding functions, respectively. affected association Shugoshin chromosomal passenger complex (CPC), without abolishing global Aurora...
The catalytic function of BUB1 is required for chromosome arm resolution and positioning the chromosomal passenger complex spindle attachment errors plays only a minor role in assembly checkpoint activation. Here, we present identification preclinical pharmacologic profile first kinase inhibitor with good bioavailability.The Bayer compound library was screened inhibitors medicinal chemistry efforts to improve target affinity physicochemical pharmacokinetic parameters resulting BAY 1816032...
Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but molecular mechanisms underlying this have not been fully clarified. Here, we show that is predominantly nuclear protein associates with network phosphatase 1 (PP1) interactors and PNUTS, regulatory subunit PP1, phosphorylated by NUAK1. Both PNUTS associate splicing machinery. Inhibition abolishes chromatin association reduces spliceosome activity, suppresses nascent RNA synthesis. Activation does bypass requirement...