The SGC Frankfurt is focused on the development and rational design of selective inhibitors (chemical probes) targeting key signaling molecules and their use for the validation of new targets. Chemical probes are cell-permeable small-molecule modulators of protein function with stringent quality criteria on potency and selectivity. (Read more)
In the framework of the IMI JU2 initiative EUbOPEN, SGC Frankfurt aims to assemble a highly annotated chemogenomics library (CGL). Chemogenomic compounds are pharmacological modulators which interact with products of the genome and alter their biological function (Read more). In contrast to chemical probes which have to fulfil stringent criteria on potency and selectivity, the potency of chemogenomic compounds is often not sufficient to be chemical probes. Thus chemogenomics compounds allow a wider spectrum of targets or target family directed chemogenomic sets.
The research teams focus on the following key research areas:
Kinases: Strategies for the development of highly specific inhibitors will be focused on a) allosteric inhibitors and inhibitors targeting unique active site pockets. This approach allows us to interrogate catalytic as well as scaffolding functions of kinases exploring also catalytically inactive or weakly active pseudokinases as drug targets; b) We are also developing covalent kinase inhibitors by targeting cysteines in the proximity of the ATP binding pocket using electrophilic groups and c) we are exploring improved shape compatibility using macrocycles to generate novel and more specific kinase inhibitors targeting the active (type I) and inactive states (type II).
Inhibitors that target key enzymes and protein-protein interactions such as bromodomains modulating chromatin and epigenetic mechanisms.
Development and characterization of chemical probes targeting the ubiquitin system.
Open science chemical probes for the research community.
The human kinome constitutes a large protein superfamily of more than 500 members. Protein kinases are deregulated in many diseases and have been therefore extensively targeted for the development of new medicines. These efforts led to the approval of more than 30 drugs during the past 15 years. However, despite the large investment of academia and pharmaceutical industry in kinase drug discovery, only a small fraction of protein kinases have been studied in detail and currently the role of most kinases in cellular signalling and in the development of diseases remains unknown. We initiated therefore a kinase chemical probe program which is a joined effort of scientists at all SGC sites, as well as a large number of academic and industrial collaborators. Goal of the program is to provide and develop the best possible chemical probes for kinase targets.
Kinase Chemical Probes
One way to understand the role of a particular kinase is to utilize a chemical probe for the kinase of interest. Small molecule chemical probes that meet stringent criteria for potency and selectivity are powerful tools to study the biology of their target proteins in cells.
Developing highly specific inhibitors for protein kinases is due to the conservation if the ATP binding site a tremendous challenge. The Frankfurt SGC laboratory is therefore particularly interested in developing allosteric kinase inhibitors that bind to target specific pockets adjacent or distantly located to the ATP site, covalent inhibitors that target unique cysteine residues as well as macrocyclic inhibitors with optimal shape compatibility to the ATP binding pocket. Allosteric inhibitors may also allow modulating scaffolding functions of kinases, an important role but poorly understood role of protein kinases that has led to unexpected signalling events of some drugs and drug candidates. Allosteric inhibitors may also allow us targeting of pseudokinases, a considerable subset of protein kinases with no or little catalytic activity that has been associated with the development of a large diversity of diseases.
Phylogenetic tree view
Phylogenetic tree displays the Kinome Tree (top) and the lipid kinase tree (bottom; tree modified from PMID: 30158316, supplementary data Fig. 1). SGC Frankfurt kinase chemical probes and donated kinase chemical probes are highlighted with a green and yellow circle, respectively. For details click the dots.
Kinase chemogenomics set
A comprehensive kinase chemogenomic set (KCGS) has been developed at the SGC UNC to inhibit the catalytic function of almost half the human protein kinases. (Drewry et al., Wells et al.)
The ‘histone code’ consisting of various modifications of amino acids located in the histone tail is one of the key regulators of gene transcription. Various proteins, such as histone acetyl transferases or histone methyl transferases ‘write’ different marks onto histones, which are then ‘read’ by other factors, such as bromodomains, which recognise acetyl lysine residues or different methyllysine binding proteins. Most histone marks can be removed by ‘eraser’ proteins such as histone deacetylases or histone lysine demethylases. Inhibitors against epigenetic proteins developed by the SGC have been the basis for compounds entering clinical trials at an unprecedented fast rate for diverse types of cancer.
The SGC chemical probe program on Epigenetic proteins, a joined effort of scientists at different SGC sites in collaboration with industrial and academic collaborators has led to a large number of high-quality selective inhibitors against several target classes. In particular, the largely underexplore family of bromodomain-containing proteins has been covered by specific chemical probes.
Bromodomain protein phylogenetic tree view
Phylogenetic tree displays the Bromodomain Tree. SGC chemical probes and donated chemical probes are highlighted with a green and yellow circle, respectively. For details click the dots.
Ubiquitin, a post-translational modification, is covalently attached to lysine residues of target proteins and modulate its function. It in turn regulates many cellular processes such as protein degradation, gene expression, translation, DNA repair, cell cycle regulation, endocytic trafficking, inflammation, and so on. Ubiquitination is a reversible modification; on one hand, the E1-E2-E3 ubiquitin enzymes bring ubiquitin to the protein substrate, on the other hand, the de-ubiquitinase (Dub) removes ubiquitin from the substrate. In the ubiquitin probe unit, we aim to discover and develop specific probes for functional and structural studies of E3 ubiquitin ligases and Dubs.
Autophagy is dedicated to the continuous renovation of intracellular components and thus plays a critical role in cellular and organismal homeostasis. It is also involved in vesicle trafficking and clearance of large intracellular structures including aggregates, dysfunctional organelles, and invading bacteria. Autophagy is frequently altered in all kind of diseases making components of the autophagy pathway a valuable target for drug development. This program targets different autophagy components including autophagy-linked kinases, autophagy receptors and individual LC3/GABARAPs to block or enhance specific canonical and non-canonical autophagy pathways.
Potent, selective and broadly characterized, small molecule chemical modulators of protein function (chemical probes), are powerful research reagents. In this unique open science project, originally initiated by several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) makes innovative high-quality probes openly available to the research community. These probes complement the probe set generated by the SGC and its academic and industry collaborators. Moreover, several probes are suitable for in vivo use. All probe and control compound-associated data and recommendations on use, are presented in a database, thereby providing both a unique resource of chemical tools and target-related knowledge in order to help researchers to decide, which chemical tools to choose, at which concentrations to use them, and how to interpret the resulting data taking into account the profiling results. To acquire a sample or the probes set, follow the link.
