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Medicinal Chemistry

AG Sippl 2022

Hugo-Junkers-Award for Research and Innovation 2026 - novel anti-cancer drugs targeting the oncogene IGF2BP1

On June 11, 2026, the Hugo Junkers Awards for Research and Innovation in Saxony-Anhalt were presented in Magdeburg. We are delighted that the project “New Cancer Therapies through Targeted Inhibition of RNA-Binding Proteins,” in collaboration with Nadine Bley and Stefan Hüttelmaier from the University Medical Center Halle, received the silver medal in the Applied Research category. Thank you to the State of Saxony-Anhalt, all the judges, and everyone in the lab for their support and excellent collaboration.

New publication on the development of potent FLT3/MAPK14 dual degraders for the treatment of leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy frequently caused by mutations in the FLT3 gene, particularly internal tandem duplications (FLT3-ITDs), which contribute to abnormal cell proliferation and resistance to tyrosine kinase inhibitors (FLT3i). The limitations of current inhibitor-based therapies highlight various issues, including drug resistance, off-target effects, and a lack of selectivity. Proteolysis-targeting chimeras (PROTACs) represent a promising approach for achieving the degradation of oncogenic proteins. In the present study, we synthesized and tested FLT3-targeting PROTACs to improve degradation efficiency and pharmacokinetic properties. The compounds MA190 and MA191, which contain rigid cyclohexyl-piperidine/piperazine linkers, demonstrate superior degradation of FLT3-ITD in MV4-11 AML cells, achieving a >95% reduction in FLT3-ITD levels. In addition to improved kinase selectivity, good solubility, and plasma stability, MA190 and MA191 also exhibit excellent metabolic stability. In cellular assays, MA190 and MA191 induce strong apoptosis in FLT3-ITD+ AML cells but have only minimal effects on cells with wild-type FLT3. Proteomic studies show that, in addition to FLT3, MA191 also degrades MAPK14 (p38α), a kinase that is upregulated in leukemia. Dual inhibition of FLT3-ITD and MAPK14 enhances proapoptotic signaling without causing cytotoxic effects in normal human HEK293 cells. Treatment with MA191 leads to greater caspase-3 activation compared to monotherapy with FLT3 or MAPK14 inhibitors. This synergistic effect could represent a therapeutic advantage, as MA191 simultaneously inactivates multiple oncogenic drivers. Further studies are planned to clarify the in vivo potential of MA191.

Abdelsalam M, Halilovic M, Ashry R, Nassar H, Erdmann F, Schmidt M, Krämer OH, Sippl W. Dual FLT3/MAPK14 Proteolysis-targeting Chimera (PROTAC) Induces Potent AML Cell Death. Pharmaceuticals (Basel). 2026;19(5):756. doi:10.3390/ph19050756   

New publication  on the development of CHK1 PROTACs in Angewandte Chemie

I am delighted to share our recent publication in Angewandte Chemie on the development and biological characterization of the first-in-class PROTAC for checkpoint kinase 1. It was a great collaboration with the Krämer group (Institute of Toxicology, University of Mainz) on another PROTAC that we developed together. Many thanks to all cooperation partners.

For the first time, we were able to develop a PROTAC molecule—MA203—that binds the target protein CHK1 to the cellular degradation machinery and initiates its proteasomal degradation. Unlike classic kinase inhibitors, which merely block enzymatic activities, MA203 eliminates the entire protein. This also disables the non-catalytic functions of CHK1, leading to increased apoptosis in tumor cells. In cell experiments, MA203 showed degradation of CHK1 in solid tumor and leukemia cells. The DNA replication stress triggered by chemotherapy further accelerates this process and enhances tumor cell apoptosis. It is noteworthy that MA203 leaves healthy hematopoietic cells, stromal cells, and retinal epithelial cells unaffected. In a direct comparison, MA203 proved to be superior to classic CHK1 kinase inhibitors currently in development – particularly with regard to the induction of DNA damage, apoptosis, and the regulation of DNA repair processes. The complete elimination of CHK1, not just its inhibition, triggers the degradation of key DNA replication and repair proteins. The study provides new insights into the non-catalytic functions of CHK1 and demonstrates the potential of PROTACs for the targeted elimination of important factors in tumor regulation.

Angewandte Chemie International Edition „Identification of a Proteolysis-Targeting Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells“.   

Two new manuscripts on drug design published in Computers in Biology and Medicine

Open access:

Baselious F, Hilscher S, Handke L, Barinka C, Schutkowski M, Sippl W. In silico screening of a designed targeted chemical space identifies novel alkyl hydrazides as potent HDAC11 inhibitors. Comput Biol Med. 2025 Jul 4;196(Pt A):110695. doi:10.1016/j.compbiomed.2025.110695   

Sarnow AC, Nassar H, Alfayomy AM, Robaa D, Sippl W. HADDOCK-Guided Modeling and Molecular Simulations of Cereblon-Based Ternary Complexes: Development of novel PROTACs for Ataxia telangiectasia and RAD3-Related (ATR) kinase. Comput Biol Med. 2025 Jun 13;194:110570. doi:10.1016/j.compbiomed.2025.110570   

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.

Over the next two years, molecules will be developed at the Department of Pharmacy at MLU in collaboration with  Prof. Dr. Julia Gallwas and Priv.-Doz. Dr. Florian Wegwitz (University of Goettingen) 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.

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.   

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