MOLECULES
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2025
·Vol. 30
·期 16
·3436
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IF 4.6
Junsong Qin,Zhepeng Chen,Chuangyan Wang,Lin Mai,Xian Wang,Junfeng Li,Hui Liu,Yun Song
This study systematically explored the interaction mechanisms between two KRAS G12C inhibitors (Sotorasib and Adagrasib) and human serum albumin (HSA) via UV-vis spectroscopy, fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, and molecular docking methods. The experimental findings demonstrated that both drugs caused static quenching of HSA fluorescence, with binding constants of 13.64 × 103M−1(Sotorasib) and 63.67 × 103M−1(Adagrasib), demonstrating significant selectivity differences in their binding affinities. UV spectral analysis demonstrated distinct microenvironmental perturbations: Sotorasib and Adagrasib induced a shift (∆λ = 7 nm and ∆λ = 8 nm, respectively) at 211 nm, consistent with altered polarity in HSA’s binding pockets. Fluorescence spectroscopy confirmed a 1:1 binding stoichiometry, with Stern-Volmer analysis validating static quenching as the dominant mechanism. Three-dimensional fluorescence spectra further highlighted Adagrasib’s stronger conformational impact, reducing tyrosine and tryptophan residue fluorescence intensities by 16% (Peak 1) and 10% (Peak 2), respectively, compared to Sotorasib. Molecular docking revealed divergent binding modes: Sotorasib occupied Sudlow Site I via three hydrogen bonds and hydrophobic interactions (∆G = −24.60 kJ·mol−1), whereas Adagrasib bound through one hydrogen bond and hydrophobic forces (∆G = −30.92 kJ·mol−1), with stability differences attributed to structural characteristics. This study uses multispectral technology and molecular docking to reveal the binding mechanism of Sotorasib and Adagrasib with HSA, providing a theoretical basis for designing highly targeted albumin nanocarriers. The strong binding properties of Adagrasib and HSA may reduce the toxicity of free drugs, providing direction for the development of long-acting formulations.
研究领域:
药理学
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生物化学
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分子生物学
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结构生物学
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药物递送系统
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-16
·
IF 7
Lu Hui,Fu Wenying,Xia Yiqun,Yan Ying,Shu Chongchong,Chen Yinghua,Xu Chenxin,Zheng Peisen,Shen Xin,Cui Ri,Zou Peng,Ni Daoyong
Adagrasib, a KRASG12C inhibitor, recently received accelerated approval from the US FDA for the treatment of patients diagnosed with KRASG12C-mutated non-small cell lung cancer. Although adagrasib has demonstrated excellent clinical efficacy and good safety, the molecular mechanism underlying the antitumor activity of adagrasib remains elusive. Here, we report that adagrasib treatment markedly inhibited the growth of cells harboring the KRASG12C mutation, whereas the non-KRASG12C cell lines H1299 and PC-9 were also sensitive to adagrasib, indicating that adagrasib exerted off-target effects. Mechanism studies indicated that adagrasib treatment reduced the level of NRF2 via upregulating its ubiquitination, and NRF2 overexpression can reverse the adagrasib-induced cell death in H23 and H1299 cells. Furthermore, adagrasib treatment significantly increased the cellular ROS level and thereby activating autophagy and AKT signaling pathways in H23 and H1299 cells. Importantly, combination of adagrasib with panobinostat demonstrated enhanced antitumor activity in vitro and in vivo. Overall, our data elucidate a novel mechanism of adagrasib, which will be critical for the clinical application of adagrasib.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Yuxin Shen,Xiaohai Chen,Hualu Wu,Hailun Xia,Ren-ai Xu
Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC 50 ) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 μM and 117.40 μM, respectively. The IC 50 value of asciminib against apixaban in RLM and HLM was 4.28 μM and 18.42 μM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs , where AUC (0-t) , AUC (0-∞) , t 1/2 , T max , and C max were increased, while CL z /F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.
研究领域:
药理学
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临床医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
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