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Medicinal Chemistry

AG Sippl 2022

Research project in collaboration with Göttingen University Medical Center wins funding from IBT Lower Saxony

The Institute for Biomedical Translation (IBT), Lower Saxony, is funding a research project with nearly one million euros over two years. The project, which is being carried out by the University Medical Center Göttingen and the Department of Pharmacy at Martin Luther University Halle-Wittenberg, focuses on the development of novel therapeutic agents for the treatment of female-specific cancers. The project impressed with its idea at the fourth IBT Portfolio Conference, held on May 13, 2025, in Hanover.

For the fourth time, the IBT Portfolio Conference took place on May 13, 2025, in Hanover. This is a funding initiative by the state of Lower Saxony to facilitate the transfer of research results into clinical practice in collaboration with the industry. A distinguished jury selected three research projects from a total of eight finalists to receive startup funding. Prof. Dr. Julia Gallwas and Priv.-Doz. Dr. Florian Wegwitz, both from the Department of Obstetrics and Gynecology at the University Medical Center Göttingen (UMG), along with Prof. Dr. Wolfgang Sippl from the Department of Pharmacy at Martin Luther University Halle-Wittenberg, won with their project “HyCan,” which focuses on the development of targeted therapies for female-specific cancers, such as endometrial, cervical, and ovarian cancers.

Over the next two years, molecules will be developed at the Department of Pharmacy at MLU to enable targeted degradation of histone deacetylases 3 and 8 (HDAC3/8). These enzymes play a crucial role in tumor growth and the spread of cancer cells. The goal is to establish a startup specializing in the development of HDAC3/8-degrading molecules for the treatment of female-specific cancers. The research project will be funded with 960,000 euros.

The HyCan Project

Cancer represents a global health challenge, with 20 million new diagnoses and 10 million deaths worldwide each year. Female-specific cancers, such as endometrial, cervical, and ovarian cancers, significantly contribute to these high figures. Treatments for these cancers, including surgeries, chemotherapy, immunotherapy, and radiation therapy, can severely impact the quality of life of patients. The HyCan project ("Hydrophobic Tag Degraders of HDAC3/8 for the treatment of Solid Cancers") focuses on histone deacetylases as a target for a novel therapeutic approach. Preliminary research shows that the enzymes HDAC3 and HDAC8 are particularly suitable targets for new therapies because they are essential for cancer cell survival, while blocking them causes minimal damage to normal cells. The HyCan team uses an innovative hydrophobic tagging technology to mark HDAC3 and HDAC8 with a “hydrophobic tag,” prompting the cell to specifically degrade these enzymes. This weakens the cancer cells while largely sparing healthy cells. Additionally, this method makes it harder for the cancer cells to develop resistance, meaning the therapy retains its effectiveness over time. "By specifically degrading HDAC3/8, we can develop more targeted and less toxic treatment methods with significant medical benefits," says Prof. Dr. Wolfgang Sippl, Head of Medical Chemistry at the Department of Pharmacy, Martin Luther University Halle-Wittenberg.

Outlook

"Thanks to the funding from the IBT, we can pursue our primary goal of developing an HDAC3/8-degrading molecule for use in patient studies to test the tolerability and safety of this new therapy. Initially, we will focus on tumors of the endometrium, cervix, and ovaries," says Prof. Gallwas. After completing the project, the team plans to spin off a company to bring the new therapy into clinical application.

For more information: www.ibt-ls.de   

New publication on FLT3-ITD PROTACs in Leukemia

Internal tandem duplications in FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). In a DFG-funded project, we have now developed two different types of degraders for FLT-ITD and characterized them biologically in leukemia cells. Nanomolar doses of the degraders, a VHL-based PROTAC (MA49) and a degrader with a hydrophobic tag (MA50) induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD, but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells and c-KIT-dependent cells. The in vivo activity of MA49 against FLT3-ITD-positive leukemia cells was demonstrated in a zebrafish model.

In mechanistic studies, we investigated the effects of the two degraders on different downstram signals. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced survival of AML patients, and HSP90, HSP110 and BIM are associated with the expression of FLT3 in primary AML cells. HSP90 suppresses degrader-induced FLT3-ITD elimination, establishing a mechanistically defined feedback loop. The two compounds represent novel, potent tools to study the chemical knockout of FLT3-ITD.

Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins.Halilovic M, Abdelsalam M, Zabkiewicz J, Lazenby M, Alvares C, Schmidt M, Brenner W, Najafi S, Oehme I, Hieber C, Zeyn Y, Bros M, Sippl W, Krämer OH. Leukemia. 2024 Sep 17. doi:10.1038/s41375-024-02405-5.   

First-in-class proteolysis targeting chimera for the Ataxia telangiectasia-and-RAD3-related kinase ATR

About three billion base pairs are replicated within each mammalian cell cycle. Chemotherapeutics kill tumor cells through the induction of DNA replication stress and DNA damage. Exogenous and endogenous DNA stress activate checkpoint kinases, which slow down the cell cycle and initiate DNA repair. The apical checkpoint kinase ataxia telangiectasia-and-RAD3-related (ATR) is activated by stalled DNA replication forks and single strand DNA breaks. Preclinical and clinical studies have demonstrated the efficacy of ATP-competitive ATR inhibitors in combination with chemotherapeutics. Proteolysis-targeting-chimeras (PROTACs) are modern agents that inhibit and eliminate their target proteins by the ubiquitin-proteasome system. We have now developed and characterized the first-in-class PROTAC for ATR in various cell systems. We demonstrate that the cereblon-targeting PROTAC Abd110 decreases ATR dependent on the E3 ubiquitin ligase cereblon and proteasomal activity. Abd110 synergistically induces apoptosis (programmed cell death) of acute myeloid and lymphatic leukemia cells when combined with the clinically used ribonucleotide reductase inhibitor hydroxyurea.

A. M. Alfayomy, R. Ashry, A. Kansy, A.C. Sarnow, F. Erdmann, M. Schmidt, O. H. Krämer, W. Sippl. Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the Ataxia telangiectasia and RAD3-related (ATR) kinase. Eur J Med Chem. 267:116167, 2024. doi:10.1016/j.ejmech.2024.116167   .

A. G. Kansy, R. Ashry,  A. M. Mustafa,  A. Alfayomy, M.P. Radsak,  Y. Zeyn, M. Bros, W. Sippl and O. H. Krämer. Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells. Mol Oncol. 2024 Mar 22. doi:10.1002/1878-0261.13638.   

New DFG Project: "Molecular Design, Synthesis, and Pharmacology of Targeted Protein Degraders for the Checkpoint Kinase ATR"

Kooperation: Prof. Dr. Oliver Krämer, Institut für Toxikologie, Johannes-Gutenbeg Universität Mainz

Preclinical cancer study: New therapeutic approach for the treatment of neuroblastoma in young children

Neuroblastome    are tumors of the nervous system and are the leading cause of cancer-related deaths in young children. A research group at the Universitätsmedizin Halle    has now uncovered the processes involved in the development of neuroblastoma for the first time. The protein IGF2BP1 is like a spark that can trigger a whole wildfire of cancer-promoting processes at the cellular level. In preclinical experiments, the researchers used a molecule that could block IGF2BP1 and nip the spark in the bud. During the development of the embryo, the protein IGF2BP1 ensures that cells can grow rapidly. If it occurs later, it is associated with tumors. "In short, IGF2BP1 ensures that another protein is produced more intensively. Both proteins can activate various, previously unexplained processes at the genetic level, which under these flawed circumstances have a strong cancer-promoting effect," explains Sven Hagemann, first author and biochemist at the Institute of Molecular Medicine at the University Medical Center Halle. In cooperation with the Institute of Pharmacy at the Martin-Luther-Universität Halle-Wittenberg   , the team has successfully tested a molecule that could block IGF2BP1.

Hagemann S, Misiak D, Bell JL, Fuchs T, Lederer MI, Bley N, Hämmerle M, Ghazy E, Sippl W, Schulte JH, Hüttelmaier S. IGF2BP1 induces neuroblastoma via a druggable feedforward loop with MYCN promoting 17q oncogene expression. Mol Cancer. 2023 May 29;22(1):88. doi:10.1186/s12943-023-01792-0   .

New DFG project in research unit RU5433 RNA in focus

The German Research Foundation is funding a new research group at the Medical Faculty of Martin Luther University Halle-Wittenberg (MLU) with seven million euros. The research focuses on specific RNA molecules and proteins that are probably involved in the formation of tumors. The goal is to understand the underlying mechanisms and thus develop new treatment approaches.

New DFG-funded project "Sirtuin-2 ligands as inhibitors of lysine long-chain deacylation and chemical tools for protein degradation" 2022-2024

Sirtuins are NAD-dependent lysine deacylases that catalyze the cleavage of acetyl but also long-chain acyl groups from lysines in histones and other substrate proteins. This post-translational modification regulates important cellular processes such as metabolism, cell proliferation or migration. The sirtuin isotype Sirtuin2 (Sirt2) has been identified as a target for drug discovery in the areas of oncology, inflammation and neurodegeneration. Dual inhibition of both deacetylation and deacylation has been postulated to be highly effective for potential anticancer drugs. In preliminary work, we have developed new lead structures for potent and selective Sirt2 inhibitors that exhibit this dual inhibition profile and block prostate cancer cell migration better than mere acetylation inhibitors. In addition, we have discovered selective inhibitors of long-chain deacylation that are unique to date. In this project, we aim to optimize the potency and cellular efficacy of dual acetylation/deacylation and selective deacylation inhibitors to further unravel the role of the different hydrolase activities of Sirt2 and exploit their therapeutic potential. In addition to "classical" inhibitors, we further intend to develop novel proteolysis-inducing chimeras (PROTACs) for Sirt2 as an orthogonal approach. These will be hybrid inhibitors that simultaneously target Sirt2 and an appropriate E3 ligase. This will lead to ubiquitinylation of Sirt2 and subsequent proteasomal degradation, which will also lead to a dual activity profile. In addition to validated ligases such as Cereblon and VHL, we will develop new ligands for the ligase Parkin, which we have discovered to be suitable for Sirt2 degradation, thus expanding the available arsenal for Sirt2 PROTACs and PROTACs in general.

Collaboration partner: Prof. Manfred Jung, Albert-Ludwigs-University of Freiburg

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