The DOI matches its Crossref record; 28 of the 30 references it cites were found in a registry or an index.
Gluing GAP to RAS Mutants: A New Approach to an Old Problem in Cancer Drug Development
Open accessAbstract
Mutated genes may lead to cancer development in numerous tissues. While more than 600 cancer-causing genes are known today, some of the most widespread mutations are connected to the RAS gene; RAS mutations are found in approximately 25% of all human tumors. Specifically, KRAS mutations are involved in the three most lethal cancers in the U.S., namely pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and lung adenocarcinoma. These cancers are among the most difficult to treat, and they are frequently excluded from chemotherapeutic attacks as hopeless cases. The mutated KRAS proteins have specific three-dimensional conformations, which perturb functional interaction with the GAP protein on the GAP–RAS complex surface, leading to a signaling cascade and uncontrolled cell growth. Here, we describe a gluing docking method for finding small molecules that bind to both the GAP and the mutated KRAS molecules. These small molecules glue together the GAP and the mutated KRAS molecules and may serve as new cancer drugs for the most lethal, most difficult-to-treat, carcinomas. As a proof of concept, we identify two new, drug-like small molecules with the new method; these compounds specifically inhibit the growth of the PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant human pancreatic cancer cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor MRTX-1133.
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KRAS-GAP molecular glue-based approaches are being explored for KRAS-targeted therapy.
“These include DARPins [71], cyclic peptides [72], KRAS–RAF protein–protein interaction inhibitors [73], and KRAS–GAP molecular glue-based approaches [74].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [74]
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Metadata
- Authors
- Ranđelović, I., Nyíri, K., Koppány, G., Baranyi, M., Tóvári, J., Kigyós, A., Tímár, J., Vértessy, B. G., & Grolmusz, V.
- Affiliations
- KINETO Lab Ltd., 1037 Budapest, Hungary
- Budapest University of Technology and Economics (HU)
- Semmelweis University (HU)
- National Institute of Oncology (HU)
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 1091 Budapest, Hungary
- Eötvös Loránd University (HU)
- Corresponding author
- Vértessy, Beáta G.
- Grolmusz, Vince
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2024-02-22
- Volume
- 25
- Issue
- 5
- Pages
- 2572
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC10932042
- OpenAlex
- W4392034832
- Cited by
- 10
- References
- 30
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 1
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- arXiv (Cornell University) (submittedVersion, cc-by)
- ELTE Digital Institutional Repository (EDIT) (Eötvös Loránd University) (submittedVersion, other-oa)
- arXiv (Cornell University) (cc-by)
- Funders
- National Research, Development, and Innovation Fund of Hungary (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- Ministry for Innovation and Technology of Hungary (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- Budapest University of Technology and Economics (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- Hungarian Thematic Excellence Programme (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- National Laboratories Excellence program (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- Hungarian National Research, Development, and Innovation Office (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- Ministry of Innovation and Technology of Hungary (PD134324, K109486, K135231, K147410, FK137867, NKP-2018-1.2.1-NKP-2018-00005, 2022-1.2.2-TÉT-IPARI-UZ-2022-00003, NVKP_16-1-2016-0020, TKP2021-EGA-02, ÚNKP-20-4 (ÚNKP-20-4-II-BME-311), TKP2021-EGA-44, 2022-2.1.1-NL-2022-00010, 2020-1.1.6-JÖVŐ-2021-00004, ELTE TKP 2021-NKTA-62)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS mutation, small molecule docking, drug discovery, pancreatic ductal adenocarcinoma, KRAS G12D, PANC-1 cells, KRAS inhibitors, anticancer drug development
- MeSH terms
- Drug Development, Adenocarcinoma, Antineoplastic Agents, Humans, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras)
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