To validate our methodology, design of Bruton's tyrosine kinase (BTK) PROTAC was selected for our case study. BTK is non-receptor tyrosine kinase that plays a role in the maturation of B cells . It represents a validated drug target in leukemia and lymphoma with well-described potent and selective ligands . Within the protein degrader field, development of BTK PROTAC was reported, owing in part to observations related to its high apparent degradability . Schiemer et al recently reported two BTK PTSs (PDB code: 6W8I/6W7O), demonstrating two distinct binding poses between the target and E3 ligase. In one PTS, the linker part is five repeated PEG units and the effective linker length is 15, and, for the other PTS, a pyrazine ring was used instead (the linker effective length is 7).