ProxiDETECT aims to develop a versatile assay, screening and molecular profiling platform for the identification and characterisation of proximity-inducing molecules, with a particular focus on molecular glues for the treatment of neurological diseases. It will expand the PROXIDRUGS toolbox to include a degrader-focused compound library, “signal-on” screening assays, novel reporter molecules, and a platform for mechanistic studies in a disease-relevant cellular context.
By exploiting the proximity principle, the project ProxiTRAPS aims to develop compounds that can be trapped specifically in cells or cell compartments (STRAPs) or highly efficiently introduced into relevant cell types (ProxiBodies). In order to achieve this, new accessory proteins as well as highly multifunctional modalities will be explored. This will be instrumental to enable a context-dependent pharmacology, which allows to reduce dose-limiting side effect.
AltTAC aims to develop a new class of molecules that use different cellular degradation pathways, such as autophagy, than the commonly used E3-based PROTACs. For this purpose small molecules with high affinity to LC3-family proteins are developed as well as protein-based high affinity binders that can recruit targets selectively to the autophagosomes. In addition, the project uses sumoylation, a special form of protein modification, to specifically improve protein solubility.
In the collaborative project AntiDEG, the partners Fraunhofer ITMP, AbbVie and the Goethe University Frankfurt/Main aim at the identification and validation of proximity-inducing small molecules for the specific degradation of neuronal target proteins and toxic protein aggregates for the treatment of neurodegenerative and neuroinflammatory diseases. In particular, the project applies human inducedpluripotent stem cell-derived cellular models of the central nervous system.
Molecular glue degraders (MGDs) are small molecules that induce protein interactions and offer unexpected possibilities for inhibiting disease-related proteins. They are much smaller than other bifunctional agents such as PROTACs, and their physicochemical properties make them more suitable as drugs. The aim of the iGLUE project is to develop new molecular adhesives by screening natural product libraries with small molecules and developing assays.
The main goal of the project NewPRO is to broaden the spectrum of E3 ligands that are available for PROTAC development. Our particular focus is on E3 ligases that show tissue-specific expression and may enable the development of drugs that preferentially degrade protein targets in diseased tissues, thereby limiting side effects. NewPRO aims also to improve the properties of new proximity-inducing molecules by reducing their size and by improving their drug-like properties.
The delivery of proximity-induced drugs is hindered by high molecular weight and unfavorable pharmakokinetic properties. The project BioDEL aims for in-depth understanding of absorption and transport processes of these molecules in human tissues (e.g. the intestine and the brain) and their in silico simulation. Based on this knowledge, customized carrier systems for targeted delivery are developed in order to enable therapeutic application of proximity-induced drugs.
As an umbrella project, InnoDATA facilitates the overall data exchange between the individual projects, develops and shapes the technology transfer and innovation strategy. Data management according to the FAIR (findability, accessibility, interoperability, and reusability)-principles will facilitate efficient data usability by all partners. New concepts for an independent cluster management in the future will be validated and established.
InnoTECH develops innovative methods and technologies for identification, characterization and optimization of proximity-induced drugs and characterizes target protein profiles by utilizing genomics, proteomics and bioinformatics The project will define proxidrug target molecules and reveal cellular resistance. Together with structural protein modeling, pipelines will be generated that define protein-molecular interaction surfaces to guide optimization.
Targeted therapies in the form of small molecule inhibitors for the treatment of cancer, sadly, have been limited in their success. Therefore, the AntiCAN project is committed to developing novel PROTACs for the treatment of cancer using modern drug design, biochemical methods and in vitro and in vivo model systems. In close cooperation with our industrial partners, the resulting drug candidates are aimed to be introduced into clinical trial within the next few years.
The AntiMIC project is engaged in the development of proximity-based agents against essential viral and bacterial factors. Such substances promise the development of a new class of therapeutics to combat multi-resistant Gram-negative bacteria and emerging viruses. This project focuses on the bacterial pathogens Salmonella spp., Legionella spp., Acinetobacter spp. and Bartonella spp. as well as on the family of coronaviruses as representatives of the viral pathogens.
Johann Wolfgang Goethe-Universität Frankfurt am Main
Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
Merck Healthcare KGaA
AbbVie Deutschland GmbH & Co. KG
Technische Universität Darmstadt
Max-Planck-Institut für Biophysik
GlaxoSmithKline Research & Development Ltd
Prof. Ivan Đikić, MD, PhD
Dr. Ingo Hartung
PD Dr. Aimo Kannt
Dr. Viktor Lakics
Prof. Dr. Maike Windbergs
Prof. Dr. Volker Dötsch
Prof. Dr. Felix Hausch
Prof. Dr. Stefan Knapp
Dr. Christian Münch
Dr. Volker Eckelt
Prof. Dr. Gerhard Hummer
Max-Planck-Institute of Biophysics
Dr. Kerstin Koch
Dr. Ole Pless
Dr. Philip Gribbon
Prof. Dr. Claudio Joazeiro
Prof. Dr. Daniela Krause
Dr. Markus Queisser