Hang on Tight: Scaling New Heights in Covalent Degrader Discovery through PK/PD Modeling
Robin T.U. Haid, Ph.D.
Last year, Robin Haid received his PhD from ETH Zurich's department of Chemistry and Applied Biosciences for his thesis on the PK/PD Modeling of Targeted Protein Degraders, which he had carried out in collaboration with Bayer in Berlin. Having joined that company as a Senior Scientist, he then went on a secondment with Vividion, a subsidiary biotech firm located in San Diego, CA. Robin has served as the modeling representative on several degrader programs, covering all phases of drug discovery and development from lead identification up to first-in-human trials. In his scientific endeavors, Robin strives to fuse mathematical rigor with the outcome-oriented mindset that drives project success, and he does so in an engaging and accessible manner. Thus, it is no wonder that colleagues in the field have adopted many of the memorable and highly expressive figures and case studies from his research articles and scientific talks for their own educational material. Outside of work, Robin enjoys the newfound freedom of post-student life and all that California has to offer, be it snorkeling with dolphins or trail running among rattle snakes.
Please note: This webinar will not be recorded and so the content will be available only on the live presentation.
Covalent ligands regularly produce strong hits in screening campaigns by attaching to shallow and cryptic pockets previously considered undruggable. Targeted protein degraders (TPDs) that covalently engage their E3 ligase, while reversibly binding the disease causing protein, preserve the catalytic mechanism of action of conventional TPDs. The PK/PD modeling of such compounds represents a unique and novel challenge, with no case studies from drug discovery projects currently available in the literature.
In vitro time course data on a covalent protein degrader could not be fully captured by the traditional indirect response models derived for non-covalent TPDs. This mismatch prompted us to adapt the mechanistic PK/PD framework by explicitly incorporating a covalent TPD–E3 ligase adduct species that persists beyond drug washout. Only once this complex has been cleared through baseline turnover can protein levels start to recover, introducing an additional delay between exposure and response.
This tailored PK/PD model accurately describes in vivo target engagement and protein degradation and allows for the extrapolation from bolus to sustained release administration. Moreover, it successfully incorporates physiological data on the baseline half-life of both the disease-causing protein and the targeted E3 ligase, boosting parameter interpretability. Due to this strong mechanistic foundation, the model can be fully informed from in vitro assays, reducing the need for expensive animal studies. By translating potency differences observed between species in vitro, the presented framework also contributes to refining human dose projections for covalent protein degraders.
This webinar empowers researchers from all backgrounds working on covalent protein degraders to pursue a quantitative understanding of their mechanism of action, and it showcases the power of PK/PD modeling in guiding study design, compound prioritization, and interspecies translation.