Drugging an undruggable pocket on KRAS
Open accessAbstract
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRAS G12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.
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Other KRAS G12D-specific inhibitors, including RMC-9805, TH-Z835, and BI2852, have been identified.
“Other inhibitors, including RMC-9805, 6 TH-Z835, 7 and BI2852, 8 have also been identified.”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [8]
The Results section identifies BI-2852 as a KRAS inhibitor and reports binding to KRASG12D. It does not support the claim that BI-2852 is G12D-specific: the same section reports similar affinity for KRAS, NRAS, and HRAS, and the Characteristics section reports inhibition in KRASG12C assays. Citation 8 is attached to BI-2852, not to the other named inhibitors. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTargeting 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 [178]
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 [178]
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 [178]
BI-2865 is a non-covalent pan-RAS inhibitor that preferentially binds to the inactive state of KRAS while preserving NRAS and HRAS, blocks nucleotide exchange, and prevents activation of wild-type KRAS and a wide range of KRAS mutations.
“This non-covalent inhibitor preferentially binds to and with high affinity to the inactive state of KRAS while preserving NRAS and HRAS HRAS [52]. It blocks nucleotide exchange to prevent the activation of wild-type KRAS as well as a wide range of KRAS mutations, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N, and A146V/T.”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [51]
The FDA has approved an allele-specific covalent inhibitor of KRAS G12C, AMG510 (sotorasib), which has marked clinical responses across multiple tumor types.
“Currently, Food and Drug Administration (FDA) has approved an allele-specific covalent inhibitor of KRAS (G12C), AMG510 (sotorasib) having marked clinical responses across multiple tumor types [21–24].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [24]
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- Authors
- Kessler, D., Gmachl, M., Mantoulidis, A., Martin, L. J., Zoephel, A., Mayer, M., Gollner, A., Covini, D., Fischer, S., Gerstberger, T., Gmaschitz, T., Goodwin, C., Greb, P., Häring, D., Hela, W., Hoffmann, J., Karolyi-Oezguer, J., Knesl, P., Kornigg, S., Koegl, M., Kousek, R., Lamarre, L., Moser, F., Munico-Martinez, S., Peinsipp, C., Phan, J., Rinnenthal, J., Sai, J., Salamon, C., Scherbantin, Y., Schipany, K., Schnitzer, R., Schrenk, A., Sharps, B., Siszler, G., Sun, Q., Waterson, A., Wolkerstorfer, B., Zeeb, M., Pearson, M., Fesik, S. W., & McConnell, D. B.
- Affiliations
- Boehringer Ingelheim (Austria) (AT)
- Vanderbilt University (US)
- Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120 Vienna, Austria;
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- McConnell, Darryl B.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-07-22
- Volume
- 116
- Issue
- 32
- Pages
- 15823-15829
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6689897
- OpenAlex
- W2963086398
- Cited by
- 449
- References
- 51
- Citations by year
- 2026: 52 · 2025: 58 · 2024: 71 · 2023: 66 · 2022: 58 · 2021: 63 · 2020: 69 · 2019: 12
- FWCI
- 17.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, DE-AC02-)
- Vanderbilt University
- Paul Scherrer Institut
- National Institutes of Health (DE-AC02–06CH11357)
- Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
- National Cancer Institute (P50A095103, DE-AC02-06CH11357, P50CA095103, RC2CA148375, P30CA068485)
- Vanderbilt Institute of Chemical Biology, School of Medicine, Vanderbilt University (P30CA68485)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357)
- 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
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- KRAS, Ras GTPase, structure-based drug design, oncogenic Ras mutations, antiproliferative activity, chemical probes
- MeSH terms
- Pharmaceutical Preparations, Guanosine Triphosphate, Humans, Models, Molecular, Proto-Oncogene Proteins p21(ras), Nanoparticles, Drug Discovery
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