Targeting protein–protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies?
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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.
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Another disadvantage of targeting the active site of kinases is that those inhibitors are highly susceptible to resistance arising from mutations in the catalytic domain, such as drug resistance to imatinib in chronic myeloid leukemia patients.
“Another disadvantage of targeting the active site of kinases is that those inhibitors are highly susceptible to resistance arising from mutations in the catalytic domain, such as drug resistance to imatinib in the case of chronic myeloid leukemia patients [4, 105].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [4]
While many cancers are driven by aberrant kinase activity, it is thought that targeting the PPIs that regulate the activity of a specific kinase is a more viable approach to develop selective kinase inhibitors than targeting the conserved ATP binding site of kinases directly.
“Furthermore, while many cancers are driven by aberrant kinase activity, it is thought that targeting the PPIs that regulate the activity of a specific kinase is a more viable approach to develop selective kinase inhibitors than targeting the conserved ATP binding site of kinases directly [4, 102, 103].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [4]
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In-silico Screening using Flexible Ligand Binding Pockets: A Molecular Dynamics-based Approach
Dakshanamurthy, S., Rajnarayanan, R. V., Doherty, J. M., et al. (2005) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-005-4788-9 · Cited by 36 · see citing works
Novel targeted drug therapies for the treatment of childhood acute leukemia
Brown, P. A., Hunger, S. P., Smith, F. O., Carroll, W. L., & Reaman, G. H. (2009) · Expert Review of Hematology · doi:10.1586/ehm.09.1 · Cited by 30 · see citing works
The Role of Academic Institutions in the Development of Drugs for Rare and Neglected Diseases
Coles, L. D., & Cloyd, J. C. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.83 · Cited by 30 · see citing works
Targeting the Human Kinome for Cancer Therapy: Current Perspectives
Zhang, L., & Daly, R. J. (2012) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.v17.i2.70 · Cited by 29 · see citing works
The evolving landscape in the therapy of acute myeloid leukemia
Peloquin, G. L., Chen, Y., & Fathi, A. T. (2013) · Protein & Cell · doi:10.1007/s13238-013-3057-2 · Cited by 26 · see citing works
The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells
Palermo, C. M., Bennett, C. A., Winters, A. C., & Hemenway, C. S. (2007) · Leukemia Research · doi:10.1016/j.leukres.2007.08.002 · Cited by 26 · see citing works
Academic drug discovery centres: the economic and organisational sustainability of an emerging model
Kirkegaard, H. S., & Valentin, F. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.06.011 · Cited by 25 · see citing works
Targeted Drug Discovery for Pediatric Leukemia
Napper, A. D., & Watson, V. G. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00170 · Cited by 19 · see citing works
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The design and development of covalent protein-protein interaction inhibitors for cancer treatment
Cheng, S.-S., Yang, G.-J., Wang, W., Leung, C.-H., & Ma, D.-L. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00850-0 · Cited by 98 · see citing works
Zhong, H.-J., Lee, B. R., Boyle, J. W., Wang, W., Ma, D.-L., Hong Chan, P. W., & Leung, C.-H. (2016) · Chemical Communications · doi:10.1039/c6cc01079b · Cited by 38 · see citing works
- Authors
- Cierpicki, T., & Grembecka, J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Grembecka, Jolanta
- Venue
- Immunological Reviews
- Publisher
- Wiley
- Published
- 2014-12-15
- Volume
- 263
- Issue
- 1
- Pages
- 279-301
- ISSN
- 0105-2896 (ISSN-L)
- 1600-065X
- PMC
- PMC4457300
- OpenAlex
- W2043842326
- Cited by
- 53
- References
- 205
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 9 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 9 · 2015: 5 · 2014: 1
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Immunological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- American Cancer Society (RSG-11-082-01-DMC, RSG-13-130-01-CDD)
- Leukemia and Lymphoma Society (6116-12, 6111-14, 1215-14)
- NIH (1R01CA160467)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- protein-protein interaction inhibitors, hematologic malignancies, small molecule inhibitors, druggability, drug discovery, cancer therapy, clinical trials
- MeSH terms
- Animals, Antineoplastic Agents, Clinical Trials as Topic, Humans, Computational Biology, Hematologic Neoplasms, Protein Interaction Domains and Motifs, Drug Discovery, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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