Cited by 459Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesComputational Drug Discovery Methods

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Drugging an undruggable pocket on KRAS

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Kessler, Dirk, Gmachl, Michael, Mantoulidis, Andreas, Martin, Laetitia J., Zoephel, Andreas, Mayer, Moriz, Gollner, Andreas, Covini, David, Fischer, Silke, Gerstberger, Thomas, Gmaschitz, Teresa, Goodwin, Craig, Greb, Peter, Häring, Daniela, Hela, Wolfgang, Hoffmann, Johann, Karolyi-Oezguer, Jale, Knesl, Petr, Kornigg, Stefan, Koegl, Manfred, Kousek, Roland, Lamarre, Lyne, Moser, Franziska, Munico-Martinez, Silvia, Peinsipp, Christoph, Phan, Jason, Rinnenthal, Jörg, Sai, Jiqing, Salamon, Christian, Scherbantin, Yvonne, Schipany, Katharina, Schnitzer, Renate, Schrenk, Andreas, Sharps, Bernadette, Siszler, Gabriella, Sun, Qi, Waterson, Alex, Wolkerstorfer, Bernhard, Zeeb, Markus, Pearson, Mark, Fesik, Stephen W., McConnell, Darryl B.·2019·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1904529116PMC PMC6689897

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Abstract

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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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: Kessler, Dirk
Gmachl, Michael
Zoephel, Andreas
Mayer, Moriz
Gollner, Andreas
Gerstberger, Thomas
Goodwin, Craig
Greb, Peter
Koegl, Manfred
Sun, Qi
Waterson, Alex
Wolkerstorfer, Bernhard
Zeeb, Markus
Pearson, Mark
Fesik, Stephen W.
McConnell, Darryl B.
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
DOI: 10.1073/pnas.1904529116
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: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › 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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Drugging an undruggable pocket on KRAS

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