Structural insights into small-molecule KRAS inhibitors for targeting KRAS mutant cancers

Pandey, Divya; Chauhan, Subhash C.; Kashyap, Vivek K.; Roy, Kuldeep K.

doi:10.1016/j.ejmech.2024.116771

Cited by 32Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

Structural insights into small-molecule KRAS inhibitors for targeting KRAS mutant cancers

Pandey, Divya, Chauhan, Subhash C., Kashyap, Vivek K., Roy, Kuldeep K.·2024·European Journal of Medicinal Chemistry

DOI 10.1016/j.ejmech.2024.116771

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Abstract

The Kirsten rat sarcoma viral (KRAS) oncogene is the most frequently mutated isoform of RAS, associated with 85 % of RAS-driven cancers. KRAS functions as a signaling hub, participating in various cellular signaling pathways and regulating a wide range of important activities, including cell proliferation, differentiation, growth, metabolism, and migration. Despite being the most frequently altered oncogenic protein in solid tumors, over the past four decades, KRAS has historically been considered "undruggable" owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design and development have culminated in the development of selective inhibitors for KRAS mutants. Recent developments have led to the successful targeting of the KRAS G12C mutant through covalent inhibitors that exploit the unique cysteine residue introduced by the mutation at 12th position. These inhibitors bind covalently to C12, locking KRAS in its inactive GDP-bound state and preventing downstream signaling. Some of these inhibitors have shown encouraging results in KRAS G12C mutant cancer patients but suffer from drug resistance, toxicity, and low therapeutic efficacy. Recently, there have been great advancements in the discovery of drugs that directly target the switch I (S-I), switch-II (S-II) and S-I/II interface sites of KRAS mutant proteins. These include KRAS G12C inhibitors like AMG510 (Sotorasib) and MRTX849 (Adagrasib), which have got FDA approval for non-small cell lung cancer harboring the KRAS G12C mutation. There is no approved drug for cancers harboring other KRAS mutations, although efforts have expanded to target other KRAS mutations and the Switch I/II interface, aiming to disrupt KRAS-driven oncogenic signaling. Structure-activity relationship (SAR) studies have been instrumental in optimizing the binding affinity, selectivity, and pharmacokinetic properties of these inhibitors, leading to the development of promising therapeutic agents like Sotorasib and Adagrasib. This review provides an overview of the KRAS pathway, KRAS binding sites, strategies for direct and indirect inhibition using small molecules, and SAR based on the co-crystal structures of inhibitors with KRAS mutants which is expected to offer new hope for patients with KRAS-driven cancers through the development of new KRAS-targeted drugs.

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The KRAS protein exhibits exceptionally high binding affinity for GTP, coupled with abundant intracellular GTP, making competitive inhibitors that displace GTP-bound KRAS exceedingly challenging.
“Firstly, the KRAS protein exhibits exceptionally high binding affinity for GTP, coupled with the abundant intracellular concentration of GTP, rendering the development of competitive inhibitors that effectively displace GTP-bound KRAS exceedingly challenging.”
From Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation (2025) · cites this paper as [6]
The absence of surface crevices suitable for small-molecule engagement defies traditional structure-based drug design paradigms.
“Secondly, the absence of surface crevices suitable for small-molecule engagement defies traditional structure-based drug design paradigms.”
From Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation (2025) · cites this paper as [6]
KRAS has retained its undruggable designation for decades, primarily attributed to two structural challenges.
“KRAS has retained its “undruggable” designation for decades, primarily attributed to two structural challenges.6”
From Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation (2025) · cites this paper as [6]

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Authors: Pandey, D., Chauhan, S. C., Kashyap, V. K., & Roy, K. K.
Affiliations: University of Petroleum and Energy Studies (IN)
The University of Texas Rio Grande Valley (US)
Corresponding author: Roy, Kuldeep K.
ORCID: Pandey, Divya
Chauhan, Subhash C.
Kashyap, Vivek K.
Roy, Kuldeep K.
Venue: European Journal of Medicinal Chemistry
Publisher: Elsevier BV
Published: 2024-11
Volume: 277
Pages: 116771
ISSN: 0223-5234 (ISSN-L)
DOI: 10.1016/j.ejmech.2024.116771
OpenAlex: W4401610637
Cited by: 32
References: 86
Citations by year: 2026: 12 · 2025: 19 · 2024: 1
FWCI: 1.30
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: European Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
ScholarWorks @ UTRGV (The University of Texas Rio Grande Valley) (submittedVersion)
Funders: University of Petroleum and Energy Studies
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: KRAS inhibitors, KRAS G12C mutation, small molecule inhibitors, covalent inhibitors, structure-activity relationship, sotorasib, adagrasib, KRAS-driven cancers, drug resistance, co-crystal structure, Ras signaling
MeSH terms: Animals, Antineoplastic Agents, Humans, Mutation, Neoplasms, Structure-Activity Relationship, Molecular Structure, Proto-Oncogene Proteins p21(ras), Small Molecule Libraries

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Structural insights into small-molecule KRAS inhibitors for targeting KRAS mutant cancers

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