Several lines of evidence suggest that target and modality selection are inseparable processes: biology and chemistry must be considered as one in drug discovery. I gave a talk at the Institute of Molecular Systems Biology at ETH about this thought, thanks to the invite by Prof. Pedro Beltrao.

The talk is motivated by two observations. First, target selection and modality selection in drug discovery have a invisibly high potential cost, and remains challenging despite great progress in biology, chemistry, and computational sciences including machine learning and artificially intelligence. Second, protein turnover, i.e. the constant synthesis and degradation of proteins, affects efficacy, potency, ADME (absorption, distribution, metabolism, and excretion) properties, and safety of drug candidates. Critically, I believe the impact of turnover on target and modality selection is currently under-appreciated, and the intrinsic link between target biology such as turnover and a drug’s efficacy and safety supports the oneness of target and modality selection.

In a review that my colleagues and I am writing, which is currently under revision, we try to illustrate why we believe that protein turnover is essential for target prioritization and modality selection, especially for emerging modalities such as covalent inhibitors and targeted protein degraders. There are still many open questions that I wish can be addressed by the community by working together.

My talk at ETH gives a glimpse of some of our thoughts, and invites both criticism and collaboration. It is built upon another talk, Defining Human Dosing for Covalent Inhibitors with Translational PK/PD and Protein Turnover Data, which I co-presented with my mentor, Neil John Parrott, in a recent DMDG meeting Focusing on Targeted Covalent Drugs: how to best identify and develop TCIs. DMDG is an informal world-wide association for scientists engaged in research and development within the drug metabolism, pharmacokinetics and related disciplines of the pharmaceutical industry.

It was a great visit, packed with the talk and many interesting discussions. I thank Prof. Beltrao and Manuela Brunner-Markl, the administrative assistant of the institute, for organizing the day.

The slides of my talk are distributed with the GPL-3 license. If you have questions, suggestions, criticism, and questions, please feel free to reach out to me.