Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer

Abstract

Targeted therapies in cancer treatment can improve in vivo efficacy and reduce adverse effects by altering the tissue exposure of specific biomolecules. However, there are still large number of target proteins in cancer are still undruggable, owing to the following factors including (1) lack of ligand-binding pockets, (2) function based on protein-protein interactions (PPIs), (3) the highly specific conserved active sites among protein family members, and (4) the variability of tertiary docking structures. The current status of undruggable targets proteins such as KRAS, TP53, C-MYC, PTP, are carefully introduced in this review. Some novel techniques and drug designing strategies have been applicated for overcoming these undruggable proteins, and the most classic and well-known technology is proteolysis targeting chimeras (PROTACs). In this review, the novel drug development strategies including targeting protein degradation, targeting PPI, targeting intrinsically disordered regions, as well as targeting protein-DNA binding are described, and we also discuss the potential of these strategies for overcoming the undruggable targets. Besides, intelligence-assisted technologies like Alpha-Fold help us a lot to predict the protein structure, which is beneficial for drug development. The discovery of new targets and the development of drugs targeting them, especially those undruggable targets, remain a huge challenge. New drug development strategies, better extraction processes that do not disrupt protein-protein interactions, and more precise artificial intelligence technologies may provide significant assistance in overcoming these undruggable targets.

Keywords: Cancer; Intrinsically disordered protein; Protein-protein interaction; Proteolysis targeting chimera; Targeted protein degradation; Undruggable target.

Figure 1

In fact, a few cancer-related targets are druggable, most are difficult to target, and often share some common characteristics.

Figure 2

Schematic diagram of mechanism of PROTACs and Lysosome-Targeting Chimaeras (LYTACs). (A)An illustration of PROTAC (Au-AR pep-PROTAC) -mediated degradation of the AR and AR-V7. (B) An illustration of LYTAC-mediated degradation.

Figure 3

Orthosteric inhibition of PPIs by SMIs and peptide inhibitors. The red dots indicate “hot spots”.