Fundamental aspects of DMPK optimization of targeted protein degraders.

Targeted protein degraders are an emerging modality. Their properties fall outside the traditional small-molecule property space and are in the ‘beyond rule of 5’ space. Consequently, drug discovery programs focused on developing orally available degraders are expected to face complex drug metabolism and pharmacokinetics (DMPK) challenges compared with traditional small molecules. Nevertheless, little information is available on the DMPK optimization of oral degraaders. Therefore, in this review, we discuss our experience of these DMPK optimization challenges and present methodologies and strategies to overcome the hurdles dealing with this new small-molecule modality, specifically in developing oral degraders to treat cancer.