Young Investigators Special with Round Table

Dr. Christian Steinebach: Leveraging induced proximity modalities for drugging epigenetic proteins

Induced proximity approaches can elicit many biological consequences. Although research on protein degraders, mostly focused on the two categories of proteolysis targeting chimeras (PROTACs) and molecular glues (MGDs), has predominated induced proximity-based drug discovery, novel branches are swiftly emerging. Bifunctional compounds that reprogram transcriptional processes lead the next generation of induced proximity technologies. Unlike protein degraders, transcriptional/epigenetic chemical inducers of proximity (TCIPs) are intended to reactivate the cells' apoptotic mechanisms. Consequently, PROTACs and TCIPs provide complementary techniques to combat cancer drivers through a "loss-of-function" or "gain-of-function" methodology.

The epigenetic control of gene expression depends on covalent, reversible, and sequence-specific changes of histone proteins that encapsulate DNA. The deregulation of this regulatory system may result in many disorders. Accordingly, histone acetyltransferases, read by bromodomain-containing proteins and erased by histone deacetylases, represent attractive drug targets. In the recent years, my lab has significantly contributed to the discovery of degraders targeting proteins associated with the epigenetic regulation of gene expression. In the first section, novel natural product-inspired PROTACs hijacking the underexplored E3 ligase KEAP1 and targeting BRD4 or the transcriptional kinase CDK9 will be presented.

Chemical tools that reprogram transcription represent a novel approach to addressing diseases like blood cancer. In diffuse large B-cell lymphoma, BCL6 functions as a transcriptional repressor that inhibits the expression of apoptosis-related genes. Nonetheless, the application of small chemical inhibitors or degraders targeting BCL6 in living beings has had modest success in clinical settings. In the second section, I will present ongoing medicinal chemistry efforts that contributed to the advancement of the TCIP concept towards novel transcriptional activators of the cellular apoptotic program. Bifunctional compounds targeting BCL6 were meticulously evaluated for their characteristics and mechanisms of action by a comprehensive assessment involving in vitro and in cellulo studies.

Dr. Clara Schoeder: Protein design as new strategy in drug discovery

Protein design is an emerging technology fueled by artificial intelligence (AI) applications. Since 2021, when AlphaFold2 was released, structure prediction and protein design rapdily evolved to become an integral part of target identification and validation. With protein design, new proteins with favorable biotechnological properties can be made without any prior knowledge except for the target structure. However, these AI protein design applications are limited by the training data, which can be very sparse for many biological problems, and explain many of the properties observed for designed proteins. Here, I will give an overview of protein design methods developed in the Schoeder Lab with some applications for drug discovery, including antigen stabilization and de novo protein design.

Dr. Lennart Brewitz: Broad-spectrum inhibitors of human 2-oxoglutarate dependent dioxygenases are useful scaffolds for rational development of selective inhibitors

Human 2-oxoglutarate (2OG)- and Fe(II)-dependent dioxygenases couple substrate oxidation to the oxidative decarboxylation of 2OG to give succinate and CO2.[1] These enzymes catalyse diverse oxidative transformations on a broad range of substrates, including RNA, DNA, proteins, and small-molecules.[1,2] Two human 2OG dioxygenases are validated drug targets, i.e., the hypoxia-inducible factor (HIF)-α prolyl residue hydroxylases 1-3 (PHD1-3) and γ-butyrobetaine hydroxylase (BBOX). Small-molecule PHD inhibitors are clinically used to treat chronic kidney disease-associated anaemia[3] and the BBOX inhibitor mildronate is clinically used as a cardioprotective agent.[4]Here we show how crystallography- and mass spectrometry-guided structure activity relationship studies on scaffolds of broad-spectrum 2OG dioxygenase inhibitors enable the development of small-molecule inhibitors with substantially improved selectivity.

Using this approach, we developed selective inhibitors of the cancer-associated Jumonji-C domain-containing protein 5 (JMJD5) based on the pyridine-2,4-dicarboxylate scaffold.[5] Furthermore, we describe strategies to enhance the selectivity of the broad-spectrum 2OG dioxygenase inhibitor BNS for inhibition of factor inhibiting HIF-α (FIH), a key component of the hypoxic response pathway alongside the PHDs.[6] Finally, we show how structural modification of the clinically used small-molecule PHD inhibitor desidustat can confer selective BBOX inhibition.[7] The developed inhibitors are valuable tools for cellular functional assignment studies and will help to improve the understanding of 2OG dioxygenases in disease. 

References:

[1] S. Martinez et al., J. Biol. Chem. 2015, 290, 20702.

[2] S. C. Fletcher et al., Biochem. Soc. Trans. 2020, 48, 1843.

[3] A. A. Joharapurkar et al., J. Med. Chem. 2018, 61, 6964.

[4] N. Sjakste et al., CNS Drug Rev. 2005, 11, 151.

[5] L. Brewitz et al., J. Med. Chem. 2023, 66, 10849.

[6] T. P. Corner et al., Chem. Sci. 2023, 14, 12098.

[7] T. P. Corner et al., J. Med. Chem. 2025, 68, 9777.