Drugging K-RasG12C through covalent inhibitors: Mission possible?
Abstract
Ras, whose mutants are present in approximately 30% of human tumours, is one of the most important oncogenes. Drugging Ras is thus regarded as the quest for the Holy Grail in cancer therapeutics development. Despite more than three decades of efforts, drug discovery targeting Ras constantly fails, rendering Ras undruggable, due to its smooth surface and picomolar affinity towards guanosine substrates. The most frequently mutated isoform of Ras is K-Ras, accounting for >85% of Ras-driven cancers, and one majority of them is the G12C mutation. Recent advances in structural biology shed light on drugging Ras, and one of the cutting-edge breakthroughs is the design of covalent G12C-specific inhibitors targeting the mutated cysteine. This type of inhibitor can be classified into substrate-competitive orthosteric inhibitors and non-competitive allosteric inhibitors. They display improved selectivity and enhanced potency due to their G12-specific and irreversible covalent binding nature. Thus, they represent a new hope for revolutionizing the conventional characterization of Ras as "undruggable" and pave a promising avenue for further drug discovery. Here, we provide comprehensive structural and medicinal chemical insights into K-Ras covalent inhibitors specific for the G12C mutant. We first present an in-depth analysis of the conformations of the inhibitor binding pockets. Then, all the latest covalent ligands selectively inhibiting K-Ras G12C are reviewed. Finally, we examine the current challenges faced by this new class of anti-Ras inhibitors.
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Adagrasib has an oral bioavailability of up to 30% and a half-life of 25 h after a single dose.
“It has an oral bioavailability of up to 30%, with a half-life of 25 h after a single dose.59”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [59]
Adagrasib is more than 1000 times more selective to KRASG12C than wild-type KRAS and other proteins containing Cys.
“Adagrasib is more than 1000 times more selective to KRASG12C than wild-type KRAS and other proteins containing Cys.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [59]
In structure-activity relationship research of 6H05 derivatives, a new allosteric pocket S-IIP was identified in KRAS and exploited in further structural optimization.
“In the research of structure-activity relationships of 6H05 derivatives, a new allosteric pocket, S-IIP, was identified in KRAS and exploited in further structural optimization.59,86”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [59]
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- Authors
- Ni, D., Li, X., He, X., Zhang, H., Zhang, J., & Lu, S.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Zhang, Jian
- Lu, Shaoyong
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 202
- Pages
- 1-17
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W2949671346
- Cited by
- 73
- References
- 119
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 6 · 2023: 13 · 2022: 13 · 2021: 17 · 2020: 11 · 2019: 9
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- National Basic Research Program of China
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- covalent inhibitors, oncogenic Ras, RAS-driven cancers, allosteric inhibitors
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Mutation, Neoplasms, Oncogenes, ras Proteins, Drug Discovery
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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