Targeting protein–protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies?

Abstract

Summary: Over the past several years, there has been an increasing research effort focused on inhibition of protein–protein interactions (PPI s) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPI s, some of which already advanced to the stage of clinical trials while others are at different stages of preclinical optimization, emphasizing PPI s as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of PPI s highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPI s and emphasize potential therapeutic benefit from blocking PPI s in hematologic malignancies. We then use these examples to discuss the approaches for successful identification of PPI inhibitors and provide analysis of the protein–protein interfaces, with the goal to address ‘druggability’ of new PPI s relevant to hematology. We discuss lessons learned to improve the success of targeting new PPI s and evaluate prospects and limits of the research in this field. We conclude that not all PPI s are equally tractable for blocking by small molecules, and detailed analysis of PPI interfaces is critical for selection of those with the highest chance of success. Together, our analysis uncovers patterns that should help to advance drug discovery in hematologic malignancies by successful targeting of new PPI s.