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

Summary Over the past several years, there has been an increasing research effort focused on inhibition of protein–protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of...

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Bibliographic Details
Published in:Immunological reviews 2015-01, Vol.263 (1), p.279-301
Main Authors: Cierpicki, Tomasz, Grembecka, Jolanta
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Clinical Trials as Topic
Computational Biology
Drug Discovery
hematologic malignancies
Hematologic Neoplasms - drug therapy
Humans
Molecular Targeted Therapy
Protein Interaction Domains and Motifs - genetics
Protein-protein interactions
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Summary:Summary Over the past several years, there has been an increasing research effort focused on inhibition of protein–protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPIs, some of which already advanced to the stage of clinical trials while others are at different stages of preclinical optimization, emphasizing PPIs as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of PPIs highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPIs and emphasize potential therapeutic benefit from blocking PPIs 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 PPIs relevant to hematology. We discuss lessons learned to improve the success of targeting new PPIs and evaluate prospects and limits of the research in this field. We conclude that not all PPIs 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 PPIs.
ISSN:0105-2896
1600-065X
DOI:10.1111/imr.12244