A5060157021- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Cancer, Hypoxia, and Metabolism
- Neuroblastoma Research and Treatments
- Cancer Research and Treatments
- Growth Hormone and Insulin-like Growth Factors
- Cell Image Analysis Techniques
- Angiogenesis and VEGF in Cancer
- Biochemical and Molecular Research
- Advanced Breast Cancer Therapies
- Cancer Mechanisms and Therapy
- Metabolism, Diabetes, and Cancer
- Immunotherapy and Immune Responses
- Peptidase Inhibition and Analysis
- Cancer Treatment and Pharmacology
- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- Cancer Immunotherapy and Biomarkers
- ATP Synthase and ATPases Research
- HIV Research and Treatment
- Ubiquitin and proteasome pathways
- Molecular Biology Techniques and Applications
- Protein Degradation and Inhibitors
- Genetic factors in colorectal cancer
- Cancer, Lipids, and Metabolism
Boehringer Ingelheim (Austria)
2008-2024
Boehringer Ingelheim (Germany)
2007
Inhibition of tumor angiogenesis through blockade the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with additional proangiogenic receptor tyrosine kinases: platelet-derived receptors (PDGFR) and fibroblast (FGFR). BIBF 1120 an indolinone derivative potently blocking VEGF (VEGFR), PDGFR FGFR kinase activity enzymatic assays (IC(50), 20-100 nmol/L). inhibits...
Abstract Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific agents with higher selectivity than approved tubulin-binding (taxanes, Vinca alkaloids), we have generated inhibitors Polo-like kinase 1, target that functions predominantly in mitosis. Experimental Design: The first compound this series, suitable i.v. administration, has entered clinical development. fully explore the...
Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule potently degrades 13 out 17 most alleles. Compared inhibition, degradation...
Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in serine synthesis pathway humans. It converts glycolysis-derived 3-phosphoglycerate 3-phosphopyruvate a co-factor-dependent oxidation reaction. Herein, we report discovery of BI-4916, prodrug co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against majority other targets. Starting with fragment-based screening, subsequent hit...
Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation PC-3 prostate carcinoma cells with an IC50 of 1 nmol/L blocks anchorage-independent proliferation EC50 3 nmol/L, whereas grown conventional surface culture are 1000-fold less...
Abstract p53 is known as the guardian of genome and one most important tumor-suppressors. It inactivated in tumors, either via tumor protein (TP53) gene mutation or copy number amplification key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to MDM2 disrupt its interaction with restore suppressor activity, thereby promoting cell cycle arrest apoptosis. Previous clinical experience MDM2–p53 protein–protein antagonists (MDM2–p53 antagonists) have demonstrated...
Despite the high prevalence of cancers driven by KRAS mutations, to date only G12C mutation has been clinically proven be druggable via covalent targeting mutated cysteine amino acid residue (1). However, in many cancer indications other such as G12D and -V, are far more prevalent small molecule concepts that can address a wider variety oncogenic alleles clinical demand (2). Here we show single used simultaneously potently degrade 13 out 17 most alleles, including those not yet tractable...
Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only BRAF- and NRAS-mutant melanoma. Improvements efficacy may be possible by combining inhibition of mitogenic signal transduction with cell-cycle progression. We studied preclinical pharmacology BI 847325, an ATP-competitive dual inhibitor Aurora kinases. Potent MEK1/2 A/B kinases 847325 was demonstrated enzymatic cellular assays. Equipotent effects were...
Abstract Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach pharmacologic intervention in cancer, owing to roles IGF1R INSRA promoting cell proliferation survival. However, central role isoform glucose homeostasis suggests that prolonged inhibition this kinase could result metabolic toxicity. We describe here profile novel compound BI 885578, a potent selective ATP-competitive IGF1R/INSR inhibitor distinguished by rapid intestinal absorption...
e13632 Background: Aurora B kinase is involved in coordinating multiple steps of mitosis, including chromosome condensation, segregation and cytokinesis. These essential functions its over-expression cancer types render this serine/threonine an attractive target for therapeutic intervention. Methods: Inhibition cell proliferation was tested Alamar blue thymidine incorporation assays. Cell-cycle status determined by DNA content analysis (FACS, Cellomics). Apoptosis analyzed Western blotting...
Abstract MDM2 inhibitors block the interaction between Tumor Protein p53 (TP53) and MDM2, its key negative regulator, represent a new therapeutic concept for cancer therapy. are designed to restore activity in TP53 wild-type tumors. Several currently being evaluated early clinical development with mainly daily dosing regimens. However, recent data suggest myelosuppression as an on-target, dose-limiting toxicity this class of inhibitors. Particularly thrombocytopenia could limit utility Hence...
Abstract MDM2 inhibitors block the interaction between Tumor Protein p53 (TP53) and MDM2, its key negative regulator, represent a new therapeutic concept in cancer therapy. are designed to restore activity TP53 wild-type tumors. Several currently being evaluated early clinical development. While tumor targeting of has been well documented, recent preclinical data with tool compound Nutlin-3 have shown that activation by local, intra-tumoral injections induces anti-tumor immunity (Cancer Res...
Abstract MDM2 inhibitors block the interaction between Tumor Protein p53 (TP53) and MDM2, its key negative regulator, represent a new therapeutic concept for cancer therapy. are designed to restore activity in TP53 wild-type tumors. Several currently being evaluated early clinical development with mainly daily dosing regimens. However, recent data suggest myelosuppression as an on-target, dose-limiting toxicity this class of inhibitors. Particularly, thrombocytopenia could limit utility...
<div>Abstract<p>p53 is known as the guardian of genome and one most important tumor suppressors. It inactivated in tumors, either via protein p53 (<i>TP53</i>) gene mutation or copy number amplification key negative regulators, e.g., mouse double minute 2 (<i>MDM2</i>). Compounds that bind to MDM2 disrupt its interaction with restore suppressor activity, thereby promoting cell cycle arrest apoptosis. Previous clinical experience MDM2–p53 protein–protein...
<p><i>In vitro</i> activity of brigimadlin in normal cells.</p>
<p>IC50 in mouse cell lines with different TP53 status.</p>
<p>MDM2 mRNA expression, copy number and brigimadlin <i>in vitro</i> activity in MDM2-amplified cell lines versus MDM2 non-amplified lines.</p>
<p>Dose-dependent regulation of p53 target genes in MDM2-amplified and non-amplified solid tumor cell lines with brigimadlin, alrizomadlin, milademetan.</p>
<p>Preliminary human PK parameters of brigimadlin.</p>
<p>TaqMan primer and probe sets used for RT-PCR.</p>
<p>Antibodies used for Western blot analysis.</p>