Inhibitors of Ras–SOS Interactions
Abstract
Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein–protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate‐limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still ‘undruggable’ for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras–SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small‐molecule modulators or peptide mimetics aimed at the interface of the Ras–SOS PPI. We emphasize, however, that even if such Ras–SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose “pathway drug cocktails”, that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.
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Designing PPI inhibitors to block the interaction of RAS and RAS effect factors represents a promising paradigm for modulating RAS function and provides new impetus for the discovery of related drugs.
“Designing PPI inhibitors to block the interaction of RAS and RAS effect factors represents a promising paradigm for modulating RAS function and provides new impetus for the discovery of related drugs.86,326–329”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [328]
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Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics
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KRAS G12C–Mutant Non–Small Cell Lung Cancer
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A New View of Pathway-Driven Drug Resistance in Tumor Proliferation
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Self-citationDrugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges
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Drugging K-RasG12C through covalent inhibitors: Mission possible?
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Self-citationOncogenic KRAS signaling and YAP1/β-catenin: Similar cell cycle control in tumor initiation
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Self-citationPersonal Mutanomes Meet Modern Oncology Drug Discovery and Precision Health
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Self-citationIntrinsic protein disorder in oncogenic KRAS signaling
Nussinov, R., Jang, H., Tsai, C., Liao, T.-J., Li, S., Fushman, D., & Zhang, J. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2564-3 · Cited by 57 · see citing works
Self-citationChakrabarti, M., Jang, H., & Nussinov, R. (2016) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5b11110 · Cited by 52 · see citing works
Self-citationTargeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure
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Blocking Ras inhibition as an antitumor strategy
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Targeting the RAS upstream and downstream signaling pathway for cancer treatment
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Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants
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Targeting KRAS mutant cancers by preventing signaling transduction in the MAPK pathway
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Liao, T.-J., Jang, H., Nussinov, R., & Fushman, D. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.9b10710 · Cited by 36 · see citing works
Self-citationAllosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles
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Self-citationLi, M.-Y., Wang, Y., Fan, J., Zhuang, H., Liu, Y., Ji, D., & Lu, S. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167730 · Cited by 31 · see citing works
Self-citationReactive Oxygen Species and Oncoprotein Signaling-A Dangerous Liaison
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K-Ras4B/calmodulin/PI3Kα: A promising new adenocarcinoma-specific drug target?
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Self-citationMechanism of activation and the rewired network: New drug design concepts
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Self-citationFragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction
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Inhibition of Nonfunctional Ras
Nussinov, R., Jang, H., Gürsoy, A., Keskin, Ö., & Gaponenko, V. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2020.12.012 · Cited by 29 · see citing works
Self-citationComputer-Aided Drug Design Boosts RAS Inhibitor Discovery
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Self-citationPan-RAS inhibitors: Hitting multiple RAS isozymes with one stone
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SOS1 interacts with Grb2 through regions that induce closed nSH3 conformations
Liao, T.-J., Jang, H., Fushman, D., & Nussinov, R. (2020) · The Journal of Chemical Physics · doi:10.1063/5.0013926 · Cited by 21 · see citing works
Self-citationXiong, Y., Zeng, J., Xia, F., Cui, Q., Deng, X., & Xu, X. (2022) · Journal of Computational Chemistry · doi:10.1002/jcc.26846 · Cited by 20 · see citing works
Calmodulin and IQGAP1 activation of PI3Kα and Akt in KRAS, HRAS and NRAS-driven cancers
Nussinov, R., Zhang, M., Tsai, C., & Jang, H. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.10.032 · Cited by 20 · see citing works
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Self-citationAdvances and Challenges in RAS Signaling Targeted Therapy in Leukemia
Chen, Y., Yin, Z., Westover, K. D., Zhou, Z., & Shu, L. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0504 · Cited by 15 · see citing works
Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect
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Nanobody Loop Mimetics Enhance Son of Sevenless 1‐Catalyzed Nucleotide Exchange on RAS**
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Assessing the mechanism of fast‐cycling cancer‐associated mutations of Rac1 small Rho GTPase
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2′-Deoxy Guanosine Nucleotides Alter the Biochemical Properties of Ras
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Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction
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RASpecting the oncogene: New pathways to therapeutic advances
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Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics
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Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance
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Evolution of structure-guided drug design strategies targeting mutations in codon 12 of KRAS
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Classification of GTP-dependent K-Ras4B active and inactive conformational states
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Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes
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Nanobody CDR3 mimetics enhance SOS1-catalyzed nucleotide exchange on RASPreprint
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- Authors
- Lu, S., Jang, H., Zhang, J., & Nussinov, R.
- Affiliations
- Shanghai Jiao Tong University (CN)
- National Cancer Institute (US)
- Tel Aviv University (IL)
- Corresponding author
- Zhang, Jian
- Nussinov, Ruth
- Venue
- ChemMedChem
- Publisher
- Wiley
- Published
- 2015-12-02
- Volume
- 11
- Issue
- 8
- Pages
- 814-821
- ISSN
- 1860-7179 (ISSN-L)
- 1860-7187
- OpenAlex
- W2187262623
- Cited by
- 72
- References
- 82
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 4 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 1
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ChemMedChem (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Basic Research Program of China
- 973 Program (2015CB910403)
- National Natural Science Foundation of China (81322046, 81302698, 81473137)
- Shanghai Rising-Star Program (13A1402300)
- Program for New Century Excellent Talents in University (NCET-12-0355)
- Shanghai Health and Family Planning Commission (20154Y0058)
- Frederick National Laboratory for Cancer Research
- National Institutes of Health (NIH) (HHSN261200800001E)
- Intramural Research Program
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- Son of Sevenless, Ras activation, guanine nucleotide exchange factor, protein-protein interaction inhibitors, RAS-mutant cancers, small molecule inhibitors, peptidomimetics, drug resistance, combination therapy
- MeSH terms
- Binding Sites, Humans, Models, Molecular, Peptides, Protein Binding, Molecular Structure, ras Proteins, Son of Sevenless Proteins, Small Molecule Libraries
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