Annual review of KRAS inhibitors in 2022

Wang, Hao; Cui, Lingling; Yu, Fuqiang; Dai, Honglin; Gao, Chao; Si, Xiaojie; Wang, Zhengjie; Liu, Limin; Zheng, Jiaxin; Shan, Lihong; Liu, Hong‐Min; Zhang, Qiurong

doi:10.1016/j.ejmech.2023.115124

Cited by 21 publications

(22 citation statements)

References 61 publications

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“…Flash chromatography was performed on silica gel (300-400 mesh, ASTM), and monitored by thin-layer chromatography (TLC) on HSGF-254 (10-40 m) TLC plates. 1 H NMR and 13 C NMR spectra were recorded on a Bruker AVII 400 spectrometer at 300 K. Spectra are calibrated relative to the residual proton and carbon chemical shifts of the solvent CDCl 3 ( 1 H,  = 7.26; 13 C,  = 77.0) as an internal standard. Data are reported as follows: chemical shift  (ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, or combinations thereof; 13 C signals are singlets unless otherwise stated), coupling constant(s) (J) in Hz, assignment.…”

Section: Scheme 5 Conformational Analysis Provides a Possible Explana...mentioning

confidence: 99%

“…1 H NMR and 13 C NMR spectra were recorded on a Bruker AVII 400 spectrometer at 300 K. Spectra are calibrated relative to the residual proton and carbon chemical shifts of the solvent CDCl 3 ( 1 H,  = 7.26; 13 C,  = 77.0) as an internal standard. Data are reported as follows: chemical shift  (ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, or combinations thereof; 13 C signals are singlets unless otherwise stated), coupling constant(s) (J) in Hz, assignment. High-resolution mass spectrometry (HRMS) was performed on a Bruker micro-TOF II ESI-TOF using positive electrospray ionization (ESI + ).…”

Section: Scheme 5 Conformational Analysis Provides a Possible Explana...mentioning

confidence: 99%

“…1,[10][11][12] Interestingly, recent research on KRAS (Kirsten rat sarcoma) inhibitor discovery suggests that trans-(2-fluorohexahydro-1H-pyrrolizin-7ayl)methanol (2), a unique 7a-substituted pyrrolizidine, is a useful fragment of several KRAS G12D inhibitors (Figure 1). 13,14 An early route to compound 2 during the drug discovery phase was stereodivergent. 15,16 Starting with ethyl pyroglutamate as ring A, it proceeded via three redox conversion steps (Scheme 1).…”

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confidence: 99%

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Syntheses of 7a-Substituted Pyrrolizidine Derivatives via Stereocontrolled Anionic Cyclization

Huang,

Chen,

Ming

et al. 2024

Synthesis

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Starting from inexpensive proline and epichlorohydrin, a pivotal stereocontrolled anionic cyclization reaction paves the way for a robust and adaptable methodology to produce stereoisomers of 7a-substituted pyrrolizidine derivatives. This process yields intriguing 7a-hydroxymethyl pyrrolizidine derivatives, among them valuable trans-(2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol, which is attainable through multiple steps.

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Section: Scheme 5 Conformational Analysis Provides a Possible Explana...mentioning

confidence: 99%

Section: Scheme 5 Conformational Analysis Provides a Possible Explana...mentioning

confidence: 99%

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confidence: 99%

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Syntheses of 7a-Substituted Pyrrolizidine Derivatives via Stereocontrolled Anionic Cyclization

Huang,

Chen,

Ming

et al. 2024

Synthesis

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“…As of 2023, there are over 70 000 papers published on the topic of KRAS, covering experimental, computational, and clinical aspects of the system. [32][33][34][35][36][37][38][39][40][41] The interaction of KRAS with other proteins and the allosteric effect of modulating distant residues, such as by mutation or drug action, are emerging as important areas of study in the field of KRAS research. Accordingly, we investigate allosteric effects, specifically anti-cooperativity and synergy, resulting from the modulation of KRAS residues on the binding characteristics of both wild-type and oncogenic KRAS-RGL1 complexes.…”

Section: Introductionmentioning

confidence: 99%

“…In the present paper, using the tools of information theory, we study the allosteric interactions of one of the most widely studied proteins, KRAS, and one its complexes. As of 2023, there are over 70 000 papers published on the topic of KRAS, covering experimental, computational, and clinical aspects of the system 32–41 . The interaction of KRAS with other proteins and the allosteric effect of modulating distant residues, such as by mutation or drug action, are emerging as important areas of study in the field of KRAS research.…”

Section: Introductionmentioning

confidence: 99%

Synergy and anti‐cooperativity in allostery: Molecular dynamics study of WT and oncogenic KRAS‐RGL1

Hacisuleyman,

Erman

2023

Proteins

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This study focuses on investigating the effects of an oncogenic mutation (G12V) on the stability and interactions within the KRAS‐RGL1 protein complex. The KRAS‐RGL1 complex is of particular interest due to its relevance to KRAS‐associated cancers and the potential for developing targeted drugs against the KRAS system. The stability of the complex and the allosteric effects of specific residues are examined to understand their roles as modulators of complex stability and function. Using molecular dynamics simulations, we calculate the mutual information, MI, between two neighboring residues at the interface of the KRAS‐RGL1 complex, and employ the concept of interaction information, II, to measure the contribution of a third residue to the interaction between interface residue pairs. Negative II indicates synergy, where the presence of the third residue strengthens the interaction, while positive II suggests anti‐cooperativity. Our findings reveal that MI serves as a dominant factor in determining the results, with the G12V mutation increasing the MI between interface residues, indicating enhanced correlations due to the formation of a more compact structure in the complex. Interestingly, although II plays a role in understanding three‐body interactions and the impact of distant residues, it is not significant enough to outweigh the influence of MI in determining the overall stability of the complex. Nevertheless, II may nonetheless be a relevant factor to consider in future drug design efforts. This study provides valuable insights into the mechanisms of complex stability and function, highlighting the significance of three‐body interactions and the impact of distant residues on the binding stability of the complex. Additionally, our findings demonstrate that constraining the fluctuations of a third residue consistently increases the stability of the G12V variant, making it challenging to weaken complex formation of the mutated species through allosteric manipulation. The novel perspective offered by this approach on protein dynamics, function, and allostery has potential implications for understanding and targeting other protein complexes involved in vital cellular processes. The results contribute to our understanding of the effects of oncogenic mutations on protein–protein interactions and provide a foundation for future therapeutic interventions in the context of KRAS‐associated cancers and beyond.

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Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies

Caughey,

Strickler

2023

Drugs

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Annual review of KRAS inhibitors in 2022

Cited by 21 publications

References 61 publications

Syntheses of 7a-Substituted Pyrrolizidine Derivatives via Stereocontrolled Anionic Cyclization

Syntheses of 7a-Substituted Pyrrolizidine Derivatives via Stereocontrolled Anionic Cyclization

Synergy and anti‐cooperativity in allostery: Molecular dynamics study of WT and oncogenic KRAS‐RGL1

Targeting KRAS-Mutated Gastrointestinal Malignancies with Small-Molecule Inhibitors: A New Generation of Breakthrough Therapies

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