KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?
Open accessAbstract
Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target. Among the different known mutations; the KRAS G12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRAS G12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRAS G12C at the cysteine at residue 12, keeping KRAS G12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.
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JNJ-74699157 is a new generation, oral, selective, covalent inhibitor of the KRASG12C subtype developed by Wellspring.
“JNJ-74699157 (4), also called ARS-3248, is a new generation, oral, selective, covalent inhibitor of the KRASG12C subtype developed by this company.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [64]
JNJ-74699157 blocks downstream signaling of KRASG12C by covalently binding to the KRASG12C complex near S-II P of the KRAS mutant protein.
“It blocks downstream signaling of KRASG12C by covalently binding to the KRASG12C complex near S-II P of the KRAS mutant protein.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [64]
The KRAS protein includes a G domain and a C-terminal membrane targeting region, and once activated through guanine nucleotide exchange factors it can affect pathways including PI3K, mTOR, RAF/MEK/ERK, and other downstream cell cycle pathways.
“The protein includes two major binding regions including the G domain and the C terminal membrane targeting region which, once activated through guanine nucleotide exchange factors (GEFs), have the ability to further affect many pathways including PI3K, mTOR, RAF/MEK/ERK, and other downstream cell cycle pathways4.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [4]
KRAS binds tightly with GTP (with picomolar affinity in vivo) in the main binding pocket, and its features sterically inhibit many treatments from reversing the strong binding affinity for GTP.
“KRAS binds tightly with GTP (with picomolar affinity in vivo) in the main binding pocket, and its features sterically inhibit many treatments from reversing the strong binding affinity for GTP4.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [4]
AMG510 is a first-in-class small molecule inhibitor of KRAS G12C that specifically and irreversibly locks KRAS in an inactive GDP binding state.
“AMG510 is a first-in-class small molecule inhibitor of KRAS (G12C) that specifically and irreversibly locks KRAS in an inactive GDP binding state, as shown in Fig. 2 [41].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [41]
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Flagged first, then by citations
Research works printed but not linked: 1
- [73]Janne PA, Papadopoulous K, Ou SI, Rybkin II and Johnson ML. A Phase 1 clinical trial evaluating the pharmacokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRAS G12C inhibitor, in advanced solid tumors. Presented at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Boston, 10 26– 30, 2019.
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Targeting KRAS mutant cancers: from druggable therapy to drug resistance
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Ghimessy, A., Radeczky, P., Laszlo, V., Hegedus, B., Renyi-Vamos, F., Fillinger, J., Klepetko, W., Lang, C., Dome, B., & Megyesfalvi, Z. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09903-9 · Cited by 115 · see citing works
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A hybrid quantum computing pipeline for real world drug discovery
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Schirripa, M., Nappo, F., Cremolini, C., Salvatore, L., Rossini, D., Bensi, M., Businello, G., Pietrantonio, F., Randon, G., Fucà, G., et al. (2020) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2020.04.009 · Cited by 66 · see citing works
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- Authors
- Nagasaka, M., Li, Y., Sukari, A., Ou, S.-H. I., Al-Hallak, M. N., & Azmi, A. S.
- Affiliations
- St. Marianna University School of Medicine (JP)
- Wayne State University (US)
- University of California, Irvine (US)
- Corresponding author
- Nagasaka, Misako
- Li, Yiwei
- Sukari, Ammar
- Ou, Sai-Hong Ignatius
- Azmi, Asfar S.
- Venue
- Cancer Treatment Reviews
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 84
- Pages
- 101974
- ISSN
- 0305-7372 (ISSN-L)
- PMC
- PMC7041424
- OpenAlex
- W3001127305
- Cited by
- 185
- References
- 78
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 25 · 2022: 35 · 2021: 57 · 2020: 29
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Treatment Reviews (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, covalent inhibitors, sotorasib, adagrasib, non-small cell lung cancer, colorectal cancer, acquired resistance, CNS activity, immune checkpoint inhibitors, combination therapy, small-molecule drug design
- MeSH terms
- Antineoplastic Agents, Humans, Mutation, Neoplasms, Prognosis, Proto-Oncogene Proteins p21(ras), Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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