Elucidation of Genome-wide Understudied Proteins targeted by PROTAC-induced degradation using Interpretable Machine Learning

Proteolysis-targeting chimeras (PROTACs) are hetero-bifunctional molecules. They induce the degradation of a target protein by recruiting an E3 ligase to the target. The PROTAC can inactivate disease-related genes that are considered as understudied, thus has a great potential to be a new type of therapy for the treatment of incurable diseases. However, only hundreds of proteins have been experimentally tested if they are amenable to the PROTACs. It remains elusive what other proteins can be targeted by the PROTAC in the entire human genome. For the first time, we have developed an interpretable machine learning model PrePROTAC, which is based on a transformer-based protein sequence descriptor and random forest classification to predict genome-wide PROTAC-induced targets degradable by CRBN, one of the E3 ligases. In the benchmark studies, PrePROTAC achieved ROC-AUC of 0.81, PR-AUC of 0.84, and over 40% sensitivity at a false positive rate of 0.05, respectively. Furthermore, we developed an embedding SHapley Additive exPlanations (eSHAP) method to identify positions in the protein structure, which play key roles in the PROTAC activity. The key residues identified were consistent with our existing knowledge. We applied PrePROTAC to identify more than 600 novel understudied proteins that are potentially degradable by CRBN, and proposed PROTAC compounds for three novel drug targets associated with Alzheimer’s disease.