The Drugit VHL Puzzle series was a set of ten puzzles released over consecutive weeks from Oct 20th, 2021 to Jan 12th, 2022. The puzzles were based on the structure of the Von Hippel-Lindau disease tumor suppressor protein in complex with ligand 10, a previously reported binder (PDB code: 5NVX) (Figure ). As all reported potent ligands, ligand 10 possesses a central hydroxyproline core motif, mimicking the natural substrate and amide-linked substituents embedded in the peptide binding groove. Players were instructed to both vary the core and find replacements as well as reduce compound polarity, provided that cellular efflux has been identified as a potential limitation of ligand 10-based PROTAC therapeutics. Particularly, the TPSA 20 was used as a proxy for efflux potential. The ten rounds of the puzzle series maintained the protein structure and the overall goals, but varied in their starting ligands, the objectives present, and the weights of their contributions (Supplementary Table ). An iterative approach was taken in determining puzzle settings. The preliminary results from each round were examined by medicinal chemists, and objectives were added or reweighted to correct 'defects' in the compounds observed. For example, in the first round, no penalty for lipophilicity of the compounds was included, leading to excessively hydrophobic compounds. The addition of an objective which penalized compounds with high clogP immediately resulted in compounds in a more desirable range in the next puzzle (Supplementary Figure ). Crystallographic waters and additional bonuses for making hydrogen bonds to those waters were also added to the starting structure when medicinal chemists felt including them would improve the quality of the submitted structures.