The small molecule BI-2852 induces a nonfunctional dimer of KRAS
Open accessAbstract
In Kessler et al. (1), the small molecule BI-2852 is shown to bind—at nanomolar affinity—to KRAS between switch I and II, inhibiting interactions with effectors. Here, we identify an alternative explanation for the inhibitory activity. While investigating the BI-2852 KRAS complex (Protein Data Bank [PDB] code 6GJ8), we noticed, by revealing the molecules in the neighboring unit cell, BI-2852 induces a KRAS dimer with rotational symmetry. This dimer complex consists of four molecules (two of BI-2852 and two of KRAS; Fig. 1 A ). Fig. 1. Dimer of KRAS with BI-2852. ( A ) Cartoon of BI-2852 KRAS dimer. Lig1 (cyan) and Lig2 (magenta) interact with both Ras1 (beige) and Ras2 (orange). ( B ) KRAS (ribbons) and key side chains are shown. ( C ) Zoom-in of the binding site: salt–bridge interactions shown (dashed lines). ( D ) Lid (green) and Basin (purple) are indicated on Ras1. Both Lig1 and Lig2 are shown on Ras1. The indole rings, colored green and purple, engage the Lid and Basin, respectively. ( E ) Absorbance A 280 plotted as a function of elution volume: … [↵][1]1To whom correspondence may be addressed. Email: trent.balius{at}nih.gov. [1]: #xref-corresp-1-1
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Targeting the switch 1/2 pocket offers the advantage, shared by MRTX1133, of hitting both GTP-bound and GDP-bound KRAS.
“This approach offers the advantage, shared by MRTX1133, of targeting both the GTP-bound and GDP-bound states of KRAS178,179.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [179]
BI-2852 is a small molecule that induces nonfunctional dimerization of KRAS.
“This pocket was initially described by Kessler et al.178,179 during the development of BI-2852, a small molecule that induces nonfunctional dimerization of KRAS.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [179]
An alternative approach targeting a switch 1/2 pocket is currently being evaluated.
“However, an alternative and unique approach of targeting a switch 1/2 pocket is currently being evaluated.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [179]
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Kessler, D., Gmachl, M., Mantoulidis, A., Martin, L. J., Zoephel, A., Mayer, M., Gollner, A., Covini, D., Fischer, S., Gerstberger, T., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1904529116 · Cited by 449 · see citing works
SI. The small molecule BI-2852 induces a non-functional dimer of KRAS
Tran, T. H., Alexander, P., Srisathiyanarayanan, D., V. Nissley, D., McCormick, F., Esposito, D., Simanshu, D. K., Stephen, A. G., & Balius, T. E. (2019) · Figshare · doi:10.6084/m9.figshare.11425995 · Cited by 1 · see citing works
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Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
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Wei, D., Wang, L., Zuo, X., Maitra, A., & Bresalier, R. S. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-2098 · Cited by 163 · see citing works
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Zhang, Z., Gao, R., Hu, Q., Peacock, H., Peacock, D. M., Dai, S., Shokat, K. M., & Suga, H. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00514 · Cited by 124 · see citing works
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Vasta, J. D., Peacock, D. M., Zheng, Q., Walker, J. A., Zhang, Z., Zimprich, C. A., Thomas, M. R., Beck, M. T., Binkowski, B. F., Corona, C. R., et al. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00985-w · Cited by 115 · see citing works
SOS GEFs in health and disease
Baltanás, F. C., Zarich, N., Rojas-Cabañeros, J. M., & Santos, E. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188445 · Cited by 100 · see citing works
Simanshu, D. K., Philips, M. R., & Hancock, J. F. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.03.008 · Cited by 55 · see citing works
Self-citationOu, A., Schmidberger, J. W., Wilson, K. A., Evans, C. W., Hargreaves, J. A., Grigg, M. C., O’Mara, M. L., Iyer, K. S., Bond, C. S., & Smith, N. M. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa262 · Cited by 49 · see citing works
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Walker, G., Brown, C., Ge, X., Kumar, S., Muzumdar, M. D., Gupta, K., & Bhattacharyya, M. (2023) · Nature Nanotechnology · doi:10.1038/s41565-023-01547-4 · Cited by 46 · see citing works
Lietman, C. D., Johnson, M. L., McCormick, F., & Lindsay, C. R. (2022) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_351333 · Cited by 44 · see citing works
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Sabt, A., Tawfik, H. O., Khaleel, E. F., Badi, R. M., Ibrahim, H. A. A., Elkaeed, E. B., & Eldehna, W. M. (2024) · Molecular Diversity · doi:10.1007/s11030-023-10777-6 · Cited by 7 · see citing works
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Gray, J. P., Bildik, G., Kim, H.-N., Sutton, M. N., Wang, J., Osuji, A. O., Batistatou, N., Yang, H., Mao, W., Tan, Z., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113686 · Cited by 1 · see citing works
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- Authors
- Tran, T. H., Alexander, P., Dharmaiah, S., Agamasu, C., Nissley, D. V., McCormick, F., Esposito, D., Simanshu, D. K., Stephen, A. G., & Balius, T. E.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- University of California, San Francisco (US)
- Corresponding author
- Balius, Trent E.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-02-11
- Volume
- 117
- Issue
- 7
- Pages
- 3363-3364
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7035607
- OpenAlex
- W3006063697
- Cited by
- 65
- References
- 2
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 10 · 2023: 13 · 2022: 6 · 2021: 10 · 2020: 8
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Cancer Institute (HHSN261200800001E)
- 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 › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS, rotational symmetry, salt bridges, protein-ligand complex structure
- MeSH terms
- Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Cell Proliferation
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