PhD position at the Institute of Physiological Chemistry, Ulm University, Germany
Job Title: PhD position at the Institute of Physiological Chemistry (TLV-E13 (65%).
Job Summary: The project is supported by a grant from the Wilhelm Sander Foundation.
Topic: "Proteolytic targeting of menin/MEN1 for the treatment of acute B-cell lymphoblastic leukemia, B-cell lymphoma and multiple myeloma".
MEN1 is a protein that regulates many cellular processes by interacting with various proteins. Inhibition of the interaction of MEN1 with the oncogenic products of MLL/KMT2A rearrangements (MLLr) by MEN1-binding inhibitors leads to clinical remissions in acute myeloid and B-cell acute lymphoblastic leukemia (AML and B-ALL) with MLLr. Unfortunately, this effect has only been observed in a subset of MLLr leukemia patients and is followed by relapse due to mutations in the KMT2A binding domain of MEN1. Since the functions of MEN1 are not limited to its interaction with KMT2A, we hypothesized that pharmacological degradation of the MEN1 protein may outperform the effect of inhibitors. This can be achieved through the use of proteolysis targeting chimeras (PROTACs), which promote targeted protein degradation. The availability of clinically tested inhibitors will enable rapid and targeted development of PROTACs. The project is based on our recent publication (Wolffhardt T. et al. Int J Mol Sci. 2023 24(22):16472) and will be carried out in collaboration with the Chemical Epigenetics research group, Institute of Pharmacological Sciences, Albert-Ludwigs-University, Freiburg.
Objectives:
Investigate the mechanisms of MEN1 dependency in B-ALLs driven by MLLr and other oncogenic mutations and identify targetable co-dependencies.
To evaluate and optimize the protein degrading activity and cytotoxic effect of MEN1-targeted PROTACs.
Investigate the activity of the most effective PROTACs against MLLr clones that have acquired resistance to MEN1 binders.
Qualifications:
Master's degree in biochemistry/biotechnology, biomedical sciences, cell biology, bioengineering or related disciplines.
Application procedure:
Please send CV by 1 February 2025. The successful candidate is expected to start no later than 1 March 2025. The position is limited to 24 months but can be extended.
Contact information:
Dr. Alexey Ushmorov, Ulm University, Institute of Physiological Chemistry, Albert-Einstein-Allee 11, 89081 Ulm Germany. Phone: +49 731 50 33847. E-mail: alexey.ushmorov@uni-ulm.de.
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