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Biomedical subjects

Ralph Mazitschek

Publications and source records attributed to Ralph Mazitschek.

10 recordsLinked to original sources
PubMed2025

A method for the detection and enrichment of endogenous cereblon substrates.

C-terminal cyclic imides are posttranslational modifications (PTMs) on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modifications across the proteome by mass spectrometry-based proteomics, an orthogonal and generalizable method to visualize the C-terminal cyclic imide would enhance detection, sensitivity, and throughput of endogenous CRBN substrate characterization. Here, we develop an antibody-like reagent, termed "cerebody," for visualizing and enriching C-terminal cyclic imide-modified proteins. We describe the engineering of CRBN derivatives to produce cerebody and use it to identify CRBN substrates by western blot and enrichment from whole-cell and tissue lysates. CRBN substrates identified by cerebody enrichment are mapped, validated, and further characterized for dependence on the C-terminal cyclic imide modification. These methods will accelerate the characterization of endogenous CRBN substrates and their regulation.

Humans↗
PubMed2003

Multistep solid-phase synthesis of an antibiotic and receptor tyrosine kinase inhibitors using the traceless phenylhydrazide linker.

The hydrazide group is an oxidatively cleavable traceless linker for solid-phase chemistry. This linker technology was used to develop a multistep solid-phase synthesis of an antibiotic that is active against Mycobacterium tuberculosis. Furthermore, we describe an efficient method for the traceless synthesis of 2-aminothiazoles that display dual inhibitory activity against the receptor tyrosine kinases VEGFR-2 and Tie-2. The synthesis method proceeds through 9 steps on the solid phase and should give access to a much larger library of 2-aminothiazoles, from which a new class of anti-angiogenesis drugs may be developed.

Anti-Bacterial Agents↗
PubMed2003

Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold.

Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC(50)s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.

Amino Acid Sequence↗
PubMed2003

Small molecules as inhibitors of cyclin-dependent kinases.

Cell division (mitosis) is one of the basic requirements for multicellular oranisms. The capability of a cell to replicate enables a complex assembly to be created. Faulty regulation of the control mechanism in the cell cycle leads to an excessive cell proliferation and is the cause of cancer. The key position of the cyclin-dependent kinases (CDKs) and their direct partners, as well as the fact that the majority of malign illnesses show defects in at least one of these key players of the cell cycle, is of great interest for the development of low-molecular-weight CDK inhibitors. In this Review an overview of the different structural classes of ATP-competitive inhibitors of CDKs are given, whose devlopment was aimed at battling cancer. The Review shows how far the development of selective CDK inhibitors has progressed and to what extent the expectations for such drugs have so far been fulfilled.

Animals↗
PubMed2002

Synthesis and biological investigation of novel tricyclic benzodiazepinedione-based RGD analogues.

Integrins, a widely expressed family of heterodimeric cell surface adhesion proteins, are expressed in a variety of cell types. They play a decisive role in cell-cell adhesion or cell to extracellular matrix adhesion events. Antagonists of alpha(v)beta(3) or alpha(IIb)beta(3) integrin may have a potential use in suppression of pathological processes. We present the synthesis of novel tricyclic benzodiazepinedione-based RGD analogues, which were subsequently tested in a solid-phase receptor assay in order to investigate their binding affinities towards alpha(v)beta(3) and alpha(IIb)beta(3) integrin.

Benzodiazepinones↗
PubMed2002

Peptidomimetics and angiogenesis.

Angiogenesis is the sprouting of new blood capillaries from surrounding preexisting blood vessels. This process is fundamental for embryonic development, wound healing and inflammation. In healthy adults angiogenesis is of minor importance. However, aberrant angiogenesis is essentially involved in disorders as diabetic retinopathy, rheumatoid arthritis and tumor growth, and blocking angiogenesis has emerged as a promising target for antagonizing these diseases. Therefore the development of new anti-angiogenic drugs is of great interest in academic and industrial research. This review focuses on the employment of peptidomimetics in inhibiting pathologic angiogenesis. It will survey the individual aspects of angiogenesis where the usage of peptidomimetics is favored and will consider the current progresses on this field.

Angiogenesis Inhibitors↗