SARCOTAC - Targeted Protein Degradation in the Heart

Advisor: Marcus Hartmann

Location: Max Planck Institute for Biology Tübingen

We offer a PhD project in our international SARCOTAC (SARCOmeric PROTAC) consortium, which formed to understand and prevent a rare but severe cardiac disease, TRIM63-related Hypertrophic Cardiomyopathy (HCM). This disease is caused by rare mutations in the TRIM63 gene, encoding an E3 ubiquitin ligase, which lead to the accumulation of sarcomeric proteins within heart cells, resulting in cardiac dysfunction. This project offers an opportunity to engage in innovative and impactful work at the intersection of cellular biology, structural biochemistry, and therapeutic development in an interdisciplinary team.

The SARCOTAC consortium is structured around three key objectives. First, we aim to develop a human heart-on-a-chip (HoC) model that replicates TRIM63-related HCM. Using patient-derived induced pluripotent stem cells, this model will enable precise disease modeling and provide a controlled platform for testing therapeutic interventions. Second, we plan to design and synthesize proteolysis-targeting chimeras (PROTACs)—a novel class of therapeutics that leverage the ubiquitin-proteasome system—to selectively degrade sarcomeric proteins implicated in HCM pathology. Third, we will evaluate these PROTAC candidates in cell culture and within the HoC system to assess their potential in reversing or mitigating cardiac hypertrophy and dysfunction.

This PhD project will focus on the design, characterization and validation of PROTAC molecules, employing a range of techniques including biophysical assays, cell culture-based experiments, and structural analysis using NMR and X-ray crystallography. Our partners in Israel will engage with patients and develop the HoC models, while chemical synthesis will be led by collaborators in Finland. Together, our consortium thus aims to develop a targeted therapy to advance personalized therapeutic options for patients with TRIM63-associated HCM.

Concept and design basis for sarcomere-directed PROTACs. A) Cardiac sarcomere structure, indicating the position of myosin (red dot) and intended sphere of ubiquitination for a myosin-binding, sarcomere-directed PROTAC (sphere). B) Design principle of a sarcomere-directed PROTAC: The myosin binding warhead should position a suitable E3 ligase bound to the E3 ligand in place to address the sarcomeric proteins in the indicated zone of ubiquitination. C) Crystal structure of β-cardiac myosin complexed with a cardiac myosin-specific drug (Mavacamten) that forms the basis for PROTAC development.

Concept and design basis for sarcomere-directed PROTACs. A) Cardiac sarcomere structure, indicating the position of myosin (red dot) and intended sphere of ubiquitination for a myosin-binding, sarcomere-directed PROTAC (sphere). B) Design principle of a sarcomere-directed PROTAC: The myosin binding warhead should position a suitable E3 ligase bound to the E3 ligand in place to address the sarcomeric proteins in the indicated zone of ubiquitination. C) Crystal structure of β-cardiac myosin complexed with a cardiac myosin-specific drug (Mavacamten) that forms the basis for PROTAC development.

More information about the research of Marcus Hartmann and a selection of recent publications can be found on his faculty page.

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Application deadline: 27 January 2025