DC 13: Establishment of novel covalent inhibitors targeting PI3K/mTOR while minimizing adverse effects

Project part of Work Package 3

Objectives: PI3K and mTOR kinase inhibition are vital strategies for limiting cell growth in mTORopathies and cancer. However, it can lead to mechanism-based adverse effects especially drug-induced insulin resistance, causing hyperglycemia and elevated insulin levels. To minimize these adverse effects, we are developing inhibitors with a durable covalent and specific action on PI3Ka while sparing PI3Kb which has a redundant function in insulin signaling. The doctoral canddiate will circumvent a partial bypass of PI3Ka inhibition observed in previous studies by concomitantly targeting the mTOR kinase in a reversible manner. This will be achieved by adapting the reversible binding module of our inhibitors, which gives rise to different selectivities across the PI3K and PIKK family as we have previously shown by > 800 structural variations. Our covalent inhibitors will be fully characterized by measuring kchem, Ki (vs. PI3K and PIKK), kinact, cellular potencies for pathway (phosphorylation of Akt, S6K, S6, 4EBP etc), growth inhibition, and more. Resistance and escape mechanisms, time on target, and re-entry into protein synthesis and translation will be evaluated. Efficacy and adverse effects will be evaluated for key compounds in in vitro and in vivo mTORopathy models.

Expected Results: Develop balanced PI3Ka/mTOR inhibitors with a long lasting covalent action on PI3Ka and rapidly reversible action on mTOR. The expected beneficial side effect profiles will make the compounds suitable as potential long term treatments in mTORopathies.

Prospects of career development: Over the past >30 years, our past lab members have acquired leading positions in academia and industry. Our proximity to Basel’s pharmaceutical industry, biotech startups, and personal interactions with present and former members of industry allows our collaborators to build early on a professional network facilitating career planning and advancement.

The candidate’s project is multidisciplinary with a strong focus on Chemical Biology, and has a translational angle to open in the best case a route to clinical development of new chemical entities. This requires that the candidate bridges the field of Medicinal Chemistry and also excels in the exploration and understanding of cellular and physiologic processes.

Planned secondments: 2 months at the University of Tübingen for exchange of covalent strategies and compound testing/validation. 3 months at BioSolveIT for mTOR/PI3K drug modelling. 2 months at IMol for screening on zebrafish brain mutants