A5103038034- Cancer Mechanisms and Therapy
- Synthesis and biological activity
- Reconstructive Surgery and Microvascular Techniques
- Reconstructive Facial Surgery Techniques
- Protein Kinase Regulation and GTPase Signaling
- Head and Neck Surgical Oncology
- Melanoma and MAPK Pathways
- Oral and Maxillofacial Pathology
- Phytochemical compounds biological activities
- Ubiquitin and proteasome pathways
- Ear and Head Tumors
- Facial Trauma and Fracture Management
- Ocular Oncology and Treatments
- Tumors and Oncological Cases
- Airway Management and Intubation Techniques
- Computational Drug Discovery Methods
- Nonmelanoma Skin Cancer Studies
- Craniofacial Disorders and Treatments
- Bone Tumor Diagnosis and Treatments
- Tracheal and airway disorders
- Cleft Lip and Palate Research
- Meningioma and schwannoma management
- Enzyme Structure and Function
- Cancer Diagnosis and Treatment
- Salivary Gland Tumors Diagnosis and Treatment
Amgen (United States)
2011-2025
Kliniken Essen-Mitte
2014-2024
University of Duisburg-Essen
2007-2024
Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie
1994-2023
Essen University Hospital
1989-2015
Leipzig University
2001-2004
Affymax (United States)
1999
Research Triangle Park Foundation
1997-1998
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable yet be identified. Here, we report efforts exploit cryptic pocket (H95/Y96/Q99) identified identify suitable for clinical development. Structure-based design leading identification novel quinazolinone scaffold are described, along with optimization that overcame...
Cellular and physiological responses to changes in dioxygen levels metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation conserved prolyl residues HIF-alpha subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement PHDs links with transcriptional regulation gene array that enables cellular response chronic hypoxia; thus act as an oxygen-sensing component system, their...
The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone that regulate glucose and lipid homeostasis. PPARγ subtype plays a central role in the regulation of adipogenesis is molecular target for 2,4-thiazolidinedione class antidiabetic drugs. Structural studies have revealed agonist ligands activate PPARs through direct interactions with C-terminal region ligand-binding domain, which includes activation function 2 helix. GW0072 was identified as high-affinity ligand weak...
Numerous indirect laryngoscopes have been introduced into clinical practice and their use for tracheal intubation under local anaesthesia has described. However, a study comparing laryngoscopic vs fibreoptic sedation appears lacking. Therefore, we evaluated both techniques in 100 patients with an anticipated difficult nasal time the primary outcome. We also assessed success rate, glottic view, Ramsey score, patients' anaesthetists' satisfaction. The median (IQR [range]) was significantly...
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of have long been known to be molecular drivers cancer. p.G12C, which occurs in approximately 14% lung adenocarcinomas, 3-5% colorectal cancers, low levels other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery a class novel, potent, selective inhibitors KRASG12C identified through custom library synthesis screening...
The kinase/endonuclease inositol requiring enzyme 1 (IRE1α), one of the sensors unfolded protein accumulation in endoplasmic reticulum that triggers response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors IRE1α endonuclease activity bound to kinase site on enzyme. Structure-activity relationship (SAR) studies led 16 and 18, which were selective screens against recombinant well cellular IRE1α. first X-ray crystal structure a inhibitor (16)...
Calcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology. Aimovig (erenumab; erenumab-aooe the United States) is only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) therapy against CGRP receptor (CGRPR) for prevention of migraine. also first FDA-approved mAb G-protein-coupled (GPCR). Here, we report architecture functional attributes erenumab critical its potent antagonism CGRPR. The crystal structure complex with CGRPR reveals direct...
Covalent inhibition of the KRASG12C oncoprotein has emerged as a promising therapeutic approach for treatment nonsmall cell lung cancer (NSCLC). The identification inhibitors typically relied on high-throughput screening (HTS) libraries cysteine-reactive small molecules or attachment warheads to noncovalent binders KRAS. Such approaches have historically been limited in size and diversity that could be effectively screened. DNA-encoded library (DEL) accelerate preparation incredibly large...
Thermodynamic measurements, structural determinations, and molecular computations were applied to a series of peptide ligands the pp60(c-src) SH2 domain in an attempt understand critical binding determinants for this class molecules. Isothermal titration calorimetry (ITC) measurements combined with data derived from X-ray crystallographic studies on 12 peptide-SH2 complexes. The studied fall into two general classes: (1) dipeptides framework N-acetylphosphotyrosine (or phosphotyrosine...
The high expression of proviral insertion site Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role promoting cell survival proliferation while suppressing apoptosis. three isoforms Pim protein appear largely redundant their oncogenic functions. Thus, pan-Pim kinase inhibitor highly desirable. However, active inhibitors have proven difficult develop because Pim-2 has low Km for ATP therefore requires...
Summary A new Airtraq ® laryngoscope has been developed for nasal intubation. We prospectively compared tracheal intubation efficiency of the nasotracheal vs that Macintosh in 200 patients. Depending on pre‐operative airway evaluation, patients were allocated to expected easy (n = 100) or difficult groups, basis mouth opening ≤ 2.5 cm, modified Mallampati score 4, history intubation, obvious tumour swelling. Patients randomly technique. All intubations successfully performed with respective...
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim inhibitors will have utility the treatment lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized potential for macrocyclization developed series 13-membered macrocycles. structure-activity relationships macrocyclic linker were systematically explored, leading to 9c as potent, subnanomolar inhibitor Pim-1 -2. This...
The p38alpha mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and variety cytokines especially interleukin-1beta tumor necrosis factor alpha. Thus, inhibitors this enzyme are postulated have significant therapeutic potential for treatment rheumatoid arthritis, inflammatory bowel disease, Crohn's as well other diseases...
Context: It is well established that clinical features of acromegaly concern the teeth and jaw, but less known about degree oral maxillofacial pathologies.