KRAS G12C fragment screening renders new binding pockets

Mathieu, Magali; Steier, Valérie; Fassy, Florence; Delorme, Cécile; Papin, David; Genet, Bruno; Duffieux, Francis; Bertrand, Thomas; Delarbre, Laure; Le-Borgne, Hélène; Parent, Annick; Didier, Patrick; Marquette, Jean‐Pierre; Lowinski, Maryse; Houtmann, Jacques; Lamberton, Annabelle; Debussche, Laurent; Alexey, Rak

doi:10.1080/21541248.2021.1979360

Cited by 15 publications

(8 citation statements)

References 41 publications

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“…Attempts to target mutant KRAS and its downstream mediators in cancer therapy remain largely unsuccessful [4,22]. However, two inhibitors efficiently targeting mutant KRAS-G12C have been developed but the clinical efficacy is yet to be determined in ongoing trials [23][24][25][26][27]. Concurrently, it has been suggested that NSCLC harboring KRAS mutations might benefit from ICB therapy compared to KRAS wild type tumors [28].…”

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confidence: 99%

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

Eklund

Wiel

Fagman

et al. 2021

Preprint

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BackgroundPembrolizumab, a humanized antibody targeting Programmed Cell Death 1 (PD-1), is used as first-line therapy for patients with metastatic Non-Small Cell Lung Cancer (NSCLC) expressing Programmed Death Ligand 1 (PD-L1). However, not all PD-L1 expressing patients respond to pembrolizumab. Thus, there is an urgent need to identify new predictive biomarkers for response to immune checkpoint blockade (ICB) therapy. KRAS mutational status has been suggested to affect treatment outcome, but no clear consensus could be drawn for previous studies.MethodsAll consecutive patients diagnosed between 2016-2018 with metastatic NSCLC (stage IV) in the region of West Sweden with molecular characterization available were included in this multi-centers retrospective study. Primary study outcome was overall survival (OS). Baseline patients’ characteristics, histology type, mutational status, PD-L1 expression and first-line treatment were collected from patient charts and the Swedish Lung Cancer registry.ResultsOut of 580 stage IV NSCLC patients, 35.5% harbored a mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.288, 95% CI 1.091-1.521, p = 0.003). When treated with first-line platinum doublet, KRASMUT (n = 219) is a significant (p = 0.001) negative factor for survival with median OS 9 months vs KRASWT 14 months. Patients on KRAS mutational status and PD-L1 expression levels had a significant better OS in KRASMUT with increased PD-L1 expression (p = 0.036) but not for KRASWT. On first-line ICB, KRASMUT had a significant (p = 0.006) better outcome than KRASWT with a median OS 23 vs 6 months. On multivariable Cox analysis, KRASMUT status and Performance Status (PS) 0-1 were independent prognostic factors for better OS (HR 0.349, 95%CI 0.148-0.822, p = 0.016 and HR 0.398, 95 % CI 0.165-0.963, p =0.041).ConclusionsKRAS mutations combined with PD-L1high is a better predictive marker for response to first-line monotherapy with pembrolizumab than only PD-L1high in patients with metastatic NSCLC.

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confidence: 99%

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

Eklund

Wiel

Fagman

et al. 2021

Preprint

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“…Clustering of the ligands reveals three clusters (A, B, and C), representing three different binding modes, including the substantial allosteric effect of this binding site (Figure b). In Cluster-A, the ligand QY5 binds into one end of the Class-III binding site between the P-loop, Switch-I, and Switch-II and has no interactions with helix α3 (Figure c) . Indeed, Switch-I deviates away from helix α3 (Figure c).…”

Section: Resultsmentioning

confidence: 99%

Analysis of KRAS–Ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics

Zhao

Bohidar

Bourne

2023

J. Chem. Inf. Model.

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KRAS, a common human oncogene, has been recognized as a critical drug target in treating multiple cancers. After four decades of effort, one allosteric KRAS drug (Sotorasib) has been approved, inspiring more KRAS-targeted drug research. Here, we provide the features of KRAS binding pockets and ligand-binding characteristics of KRAS complexes using a structural systems pharmacology approach. Three distinct binding sites (conserved nucleotide-binding site, shallow Switch-I/II pocket, and allosteric Switch-II/α3 pocket) are characterized. Ligand-binding features are determined based on encoded KRAS–inhibitor interaction fingerprints. Finally, the flexibility of the three distinct binding sites to accommodate different potential ligands, based on MD simulation, is discussed. Collectively, these findings are intended to facilitate rational KRAS drug design.

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“…Clustering of the ligands reveals three clusters (A, B, and C), representing three different binding modes, including the substantial allosteric effect of this binding site (Figure 5b). In Cluster-A, the ligand QY5 binds into one end of the Class-III binding site between the P-loop, Switch-I, and Switch-II, and has no interactions with helix α3 (Figure 5c) 32 . Indeed, Switch-I deviates away from helix α3 (Figure 3c).…”

Section: Resultsmentioning

confidence: 99%

Systematic Analysis of KRAS-ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics

Zhao

Bohidar

Bourne

2023

Preprint

View full text Add to dashboard Cite

KRAS, a common human oncogene, has been recognized as a critical drug target in treating multiple cancers. After four decades of effort, one allosteric KRAS drug (Sotorasib) has been approved, inspiring more KRAS-targeted drug research. Here we provide the features of KRAS binding pockets and ligand-binding characteristics of KRAS complexes using a structural systems pharmacology approach. Three distinct binding sites (conserved nucleotide-binding site, shallow Switch-I/II pocket, and allosteric Switch-II/α3 pocket) are characterized. Ligand-binding features are determined based on encoded KRAS-inhibitor interaction fingerprints. Finally, the flexibility of the three distinct binding sites to accommodate different potential ligands, based on MD simulation, is discussed. Collectively, these findings are intended to facilitate rational KRAS drug design.

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KRAS G12C fragment screening renders new binding pockets

Cited by 15 publications

References 41 publications

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

KRASmutations impact clinical outcome in metastatic non-small cell lung cancer

Analysis of KRAS–Ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics

Systematic Analysis of KRAS-ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics

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