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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DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-15
·
IF 7
Cheng Mengting,Wu Wentong,Li Qing,Tao Xinyu,Jiang Feng,Li Jinjin,Shen Nonger,Wang Fei,Luo Peihua,He Qiaojun,huang Ping,Xu Zhifei,Zhang Yiwen
Sotorasib, the inaugural targeted inhibitor sanctioned for the management of patients afflicted with locally advanced or metastatic non-small cell lung cancer presenting the KRAS G12C mutation, has encountered clinical application constraints due to its potential for cardiac injury as evidenced by safety trials. This investigation has elucidated that the heightened expression of neuraminidase-1 (NEU1) constitutes the principal etiology of cardiac damage induced by sotorasib. Mechanistically, sotorasib treatment inhibited the ubiquitinated degradation of NEU1, leading to its elevated expression, which induced downstream AKT signaling pathway inhibition and mitochondrial dysfunction leading to cardiomyocyte apoptosis. Meanwhile, in vivo and in vitro studies showed that D-pantothenic acid (D-PAC) alleviated sotorasib-induced cardiac damage by promoting NEU1 degradation. In conclusion, this study revealed that NEU1 is a key protein in sotorasib cardiotoxicity and that reducing the level of this protein is a critical strategy for the clinical treatment of sotorasib-induced cardiac injury. Schematic representation of a mechanism.
研究领域:
肿瘤学
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心脏病学
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分子生物学
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药理学
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Jiajia Chen,Xiaoxiao Liu,Ruoyu Wang,Jinjin Li,Zhifei Xu,Bo Yang,Qiaojun He,Xiaochun Yang,Hao Yan,Peihua Luo
Sotorasib, a first-in-class KRAS G12C inhibitor, has demonstrated substantial clinical efficacy in KRAS G12C–mutant malignancies but is frequently associated with gastrointestinal adverse events, the mechanisms of which remain poorly understood. In this study, we investigated the molecular basis of sotorasib-induced intestinal toxicity using complementary in vitro and an HP-β-CD-optimized in vivo model. Sotorasib treatment disrupted intestinal epithelial homeostasis by promoting apoptosis and suppressing proliferative capacity, resulting in impaired epithelial barrier integrity. Mechanistically, sotorasib markedly suppressed intracellular cAMP signaling in intestinal epithelial cells, as evidenced by reduced protein kinase A (PKA) activity and decreased phosphorylation of the transcription factor CREB. These effects were consistently observed in IEC-6 cells and murine colonic tissues lacking the KRAS G12C mutation, indicating a KRAS-independent mechanism. Pharmacological elevation of intracellular cAMP with forskolin partially restored CREB phosphorylation, attenuated epithelial apoptosis, enhanced proliferative activity, and improved expression of barrier-associated markers. In contrast, in NCI-H358 cells, forskolin increased CREB phosphorylation but failed to rescue sotorasib-induced growth inhibition, highlighting a pronounced cell type-dependent response to sotorasib. Collectively, our findings identify suppression of the cAMP/PKA/CREB signaling axis as a key mechanism underlying sotorasib-induced intestinal epithelial injury and provide mechanistic insight into the tissue-selective gastrointestinal toxicity of KRAS G12C-targeted therapy
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高影响因子
Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-18
·
IF 8.9
Zhang Jiaqi,Li Jinjin,Cheng Mengting,Zhou Haiyang,Zhang Xiaochen,Yan Hao,Xu Zhifei,Yang Bo,He Qiaojun,Gao Zizheng,Chen Xueqin,Luo Peihua
Sotorasib, the first FDA-approved KRAS G12C inhibitor, has demonstrated remarkable clinical efficacy in non-small cell lung cancer (NSCLC). However, its clinical utility is hampered by life-threatening interstitial lung disease (ILD), whose molecular basis remains unknown. Through the integration of transcriptomic and metabolomic analyses, we revealed that sotorasib activates PPAR-γ signaling, upregulating fatty acid oxidation (FAO) via its downstream effector CPT1B. This metabolic shift triggered mitochondrial ROS overproduction, which drives alveolar epithelial apoptosis and fibrosis in vivo and in vitro . Mechanistically, sotorasib directly binds to PPAR-γ via Thr325, facilitated by FABP4-mediated nuclear translocation, amplifying its transcriptional activity via a feedforward loop. Pharmacological inhibition of FABP4 attenuated PPAR-γ activation, mitigated ROS-driven apoptosis, and rescued pulmonary fibrosis in mice. Taken together, these findings identify the FABP4-PPARγ-CPT1b axis as a novel off-target mechanism of sotorasib-induced lung toxicity and propose FABP4 inhibition as a promising therapeutic target to enhance its clinical safety.
Section
Graphical
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高影响因子
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