DC 14: Optimization of S6K2-Selective Inhibitors for In Vivo Application

Project part of Work Package 3

Objectives: The p70 ribosomal protein S6 kinases S6K1 (RPS6KB1) and S6K2 (RPS6KB2) are major downstream effectors of the mTOR complex 1 (mTORC1). While the role of S6K1 is well studied, at least in cancer, knowledge on S6K2 function remains severely limited, especially in the context of mTORopathies. Investigation of S6K2 as a potential drug target is hampered by a lack of isoform-selective S6K2 inhibitors to dissect S6K1 and S6K2 functions. We recently reported the first selective S6K2 inhibitor which relies on a S6K2-specific covalent binding mechanism. DC14 aims at optimizing our S6K2 inhibitors for application in vivo, with a special emphasis in brain penetration. DC14 will improve the solubility and identify/mitigate metabolic hotspots, while maintaining potency and selectivity. In conjunction with molecular modelling, optimization will be guided by enzyme and reactivity assays, physicochemical property profiling and testing of in vitro absorption, distribution, metabolism, and excretion (ADME) properties (e.g. microsomal stability, permeability and efflux). In vivo PK/PD profiling of key compounds will be performed with collaborators from this consortium and the optimized inhibitors will be provided to partners for functional in vivo studies.

Expected Results: We will develop highly potent and exquisitely isoform-selective S6K2 inhibitors with suitable ADME properties for in vivo application. Thereby, we will provide tools for the validation of S6K2 as a potential drug target in different mTORopathies and a basis for further translational studies and drug development efforts.

Prospects of career development: To support individual career development, the University of Tübingen provides a wide range of seminars, courses, and mentoring opportunities, in addition to those offered through the MENTOR network. These resources are designed to promote professional growth and ensure long-term career success.

The Gehringer group is highly visible within the field of medicinal chemistry, fostering strong connections with both academia and industry. The PhD position offers a comprehensive, interdisciplinary education, along with opportunities to regularly attend scientific conferences to network and present research findings. Graduates of the Gehringer lab are expected to be competitively positioned on the European job market, equipped with a robust skill set and professional network gained through their PhD training.

Planned secondments: 1 month at the University of Basel to learn complementary covalent targeting approaches; 1 month at PD-value for modelling of PK/PD properties; 3 months at BiosolveIT for structure-based drug design