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Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs
Open accessAbstract
Here, we discuss the principles of allosteric activating mutations, propagation downstream of the signals that they prompt, and allosteric drugs, with examples from the Ras signaling network. We focus on Abl kinase where mutations shift the landscape toward the active, imatinib binding-incompetent conformation, likely resulting in the high affinity ATP outcompeting drug binding. Recent pharmacological innovation extends to allosteric inhibitor (GNF-5)-linked PROTAC, targeting Bcr-Abl1 myristoylation site, and broadly, allosteric heterobifunctional degraders that destroy targets, rather than inhibiting them. Designed chemical linkers in bifunctional degraders can connect the allosteric ligand that binds the target protein and the E3 ubiquitin ligase warhead anchor. The physical properties and favored conformational state of the engineered linker can precisely coordinate the distance and orientation between the target and the recruited E3. Allosteric PROTACs, noncompetitive molecular glues, and bitopic ligands, with covalent links of allosteric ligands and orthosteric warheads, increase the effective local concentration of productively oriented and placed ligands. Through covalent chemical or peptide linkers, allosteric drugs can collaborate with competitive drugs, degrader anchors, or other molecules of choice, driving innovative drug discovery.
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“Due to its higher specificity and consequently lower toxicity, which results from targeting nonconserved allosteric sites, allostery also increasingly features in allosteric drugs.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [121]
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Citations
Cites
ON THE NATURE OF ALLOSTERIC TRANSITIONS: A PLAUSIBLE MODEL.
Monod, J., Wyman, J., & Changeux, J. (1965) · Journal of Molecular Biology · doi:10.1016/s0022-2836(65)80285-6 · Cited by 7,681
The Energy Landscapes and Motions of Proteins
Frauenfelder, H., Sligar, S. G., & Wolynes, P. G. (1991) · Science · doi:10.1126/science.1749933 · Cited by 3,250
Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.141230798 · Cited by 2,609
Dynamic personalities of proteins
Henzler-Wildman, K., & Kern, D. (2007) · Nature · doi:10.1038/nature06522 · Cited by 2,545
From Levinthal to pathways to funnels
Dill, K. A., & Chan, H. S. (1997) · Nature Structural & Molecular Biology · doi:10.1038/nsb0197-10 · Cited by 2,293
THEORY OF PROTEIN FOLDING: The Energy Landscape Perspective
Onuchic, J. N., Luthey-Schulten, Z., & Wolynes, P. G. (1997) · Annual Review of Physical Chemistry · doi:10.1146/annurev.physchem.48.1.545 · Cited by 2,210
RAS oncogenes: weaving a tumorigenic web
Pylayeva-Gupta, Y., Grabocka, E., & Bar-Sagi, D. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3106 · Cited by 1,789
Shared and distinct transcriptomic cell types across neocortical areas
Tasic, B., Yao, Z., Graybuck, L. T., Smith, K. A., Nguyen, T. N., Bertagnolli, D., Goldy, J., Garren, E., Economo, M. N., Viswanathan, S., et al. (2018) · Nature · doi:10.1038/s41586-018-0654-5 · Cited by 1,746
Hyperactive Ras in developmental disorders and cancer
Schubbert, S., Shannon, K., & Bollag, G. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2109 · Cited by 1,583
Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions
Kölch, W. (2000) · Biochemical Journal · doi:10.1042/bj3510289 · Cited by 1,443
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Li, Z., Xi, Y., Tu, L., Zhang, X., Huang, Y., Nie, H., Peng, C., Chai, H., Zeng, S., Zheng, X., et al. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116315 · Cited by 3
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Metadata
- Authors
- Nussinov, R., Zhang, M., Maloney, R., Liu, Y., Tsai, C.-J., & Jang, H.
- Affiliations
- Tel Aviv University (IL)
- Frederick National Laboratory for Cancer Research (US)
- Corresponding author
- Nussinov, Ruth
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 434
- Issue
- 17
- Pages
- 167569
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC9398924
- OpenAlex
- W4220688241
- Cited by
- 66
- References
- 294
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 12 · 2023: 11 · 2022: 9
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Frederick National Laboratory for Cancer Research
- National Institutes of Health (HHSN261201500003I)
- U.S. Department of Health and Human Services
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ras signaling, c-Abl, PROTACs, chemical linkers, E3 ubiquitin ligase, molecular glues, bitopic ligands, drug discovery
- MeSH terms
- Allosteric Regulation, Antineoplastic Agents, Humans, Ligands, Mutation, Neoplasms, Fusion Proteins, bcr-abl, Protein Kinase Inhibitors, Drug Discovery, Proteolysis
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