CRYSTAL GROWTH & DESIGN
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2026
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IF 3.6
Hanzi Zheng,Kaxi Yu,Dier Shi,Shuna Liu,Yifan Zhao,Jiyong Liu,Xiurong Hu
Salt formation proved to be the most effective solid-state form for insoluble drugs in terms of improving solubility, crystallinity, stability, and/or bioavailability. A salt form of a drug where two ions of the same type are associated with one drug molecule further improves solubility and overall drug performance. However, a systematic comparison of these forms for a given drug combination remains scarce. This is achieved by the drug having at least two sites that can ionize, allowing it to form ionic bonds with a counterion. Osimertinib (OSTN), characterized by poor solubility and bioavailability, is a highly selective kinase inhibitor approved by the FDA, which is indicated for treatment of locally advanced or metastatic nonsmall cell lung cancer. In the present study, a multicomponent system based on OSTN’s diprotic base was prepared and characterized by various methods. This system comprises mono- and disalts derived from three sulfonic acids: methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Although the powder diffractions of OSTN mesylate (OSTN-MSA-A and OSTN-MSA-B) and OTSN tosilate (OSTN-TsOH) have been reported, and the crystal structure of OSTN-MSA-B was solved by using synchrotron X-ray powder diffraction data and optimized using density functional techniques, our study marks the inaugural report of their crystallographic structures. Three new solid forms (OSTN-BES, OSTN-2BES, and OSTN-2TsOH) were initially identified and subjected to a comprehensive characterization through thermal analysis, X-ray diffraction, X-ray photoelectron spectroscopy (XPS) techniques, etc. In addition, their hygroscopicity and solubility were determined and compared, combining with the respective molecular conformation, their inter- and intramolecular interactions, and packing arrangement. Notably, OSTN disalt exhibited superior dissolution performance when compared to that of monosalt. The comparative study offers valuable guidance for the development of salt screening for insoluble drugs with two sites that can ionize.
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高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Yuying Wang,Quanwei Yu,Xiongqi Yang,Lingling Ma,Ridong Huang,Hai Chen,Zhonghua Jiang,Zhenru Wu,Chengyong Wu,Xuemei Deng,Jing Wang,Weimin Li,Yang He
The tertiary C797S mutation in the EGFR tyrosine kinase domain disrupts osimertinib binding, driving resistance in NSCLC. We designed a series of novel diaminopyrimidine derivatives to establish the interaction with Ser797. H8b potently inhibited EGFRL858R/T790M/C797S kinase with an IC50 of 3.86 nM (30-fold lower than osimertinib) and suppressed both double mutant NCI-H1975 and triple mutant H1975-M3 cells with IC50s of 0.03 μM and 0.57 μM (14- and 11-fold reductions over osimertinib, respectively). Cocrystal X-ray analysis revealed that H8b forms a “two-point tethering” in the ATP pocket with a hydrogen bond between its dichloropropionamide oxygen and Ser797, complemented by a hydrogen bond between terminal N of the piperazine ring and Phe795. Mechanistically, H8b suppressed EGFR phosphorylation and downstream AKT, STAT3, and MAPK signaling, inhibiting proliferation, invasion, and migration. In vivo, H8b achieved 71.15% tumor inhibition in H1975-M3 xenografts. This study identifies H8b as a promising EGFR-TKI overcoming C797S-mediated resistance.
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高影响因子
Journal of Thoracic Disease
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2023
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IF 2.5
Dianbao Zhang,Yukun Yang,Yixin Kang,Dongjie Xie,Xianfen Zhang,Jiqing Hao
Background An increasing amount of evidence has confirmed that the altered expression of microRNAs (miRNAs) is critical to the mechanism underlying primary and even acquired resistance to tyrosine kinase inhibitors (TKIs). However, studies on the linkage between the altered miRNAs expression and osimertinib resistance are few, and the effect of miRNAs in this context is still unclear. In the light of this, we hypothesized that the differential expression of multiple miRNAs is the driver in the osimertinib resistance process. Thus, the aim of our study was to find differentially expressed miRNAs in non-small cell lung cancer cells resistant to osimertinib. Methods An AZD9291(Osimertinib)-resistant cell line model was constructed, and the differential miRNAs between epidermal growth factor receptor (EGFR)-sensitive cell lines A549 and H1975 and the corresponding drug-resistant cell lines were identified via biosynthesis analysis. Results In the A549 osimertinib-resistant cell line, 93 miRNAs were upregulated and 94 miRNAs were downregulated. In the H1975 osimertinib-resistant cell line, 124 miRNAs were upregulated and 53 miRNAs were downregulated. Finally, 7 significantly different miRNAs were screened using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Conclusions This study on the mechanism of target therapy in lung cancer systematically and comprehensively examined the miRNAs involved in osimertinib resistance. It was found that miR-708-5p, miR-708-3p, miR-10395-3p, miR-7704 miR-34a-5p, miR-19b-1-5p, and miR-219a-5p may play key roles in osimertinib resistance.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ACS Pharmacology & Translational Science
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2025
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IF 3.7
Yizhen Guo,Ding Huang,Yan Zhou,Maoxin Ran,Shaolin Zhang,Kin Yip Tam
Acquired resistance to osimertinib (OSI) poses a significant challenge in the treatment of epidermal growth factor receptor mutant non-small cell lung cancer (NSCLC). Although OSI is effective as a first-line salvage therapy in T790M-positive patients following progression on first- or second-generation EGFR-TKIs (erlotinib, gefitinib, and afatinib), the inevitable development of acquired resistance limits its therapeutic efficacy. This study reveals that OSI-resistant (OSIR) NSCLC cells underwent metabolic reprogramming characterized by enhanced glycolysis and upregulation of hexokinase 2 (HK2). We demonstrated that HK2 inhibitor, benserazide, exhibited significant anticancer effects in OSIR cell models and mediated by reactive oxygen species. Our results suggested that HK2 inhibition effectively modulated the enhanced glycolysis, activated the AMPK-mTOR-autophagy axis, and unexpectedly interfered with NF-κB signaling through direct HK2-IKKβ interaction. Excitingly, the protein expression level and activity of pyruvate dehydrogenase kinase 1 (PDK1) in OSIR cells were upregulated upon HK2 inhibition, indicating a pro-survival role. Combined inhibition of HK2 and PDK1 synergistically inhibited the proliferation of OSIR cells and significantly suppressed tumor growth in an OSIR cell xenograft model, outperforming the single use of HK2 inhibitor. This combination successfully rectified aberrant glucose metabolism and enhanced oxidative phosphorylation. Our findings identified HK2 as a crucial mediator in overcoming OSI resistance and suggested that combined inhibition of HK2 and PDK1 could be a promising approach in OSIR NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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生物化学
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PubMed
高影响因子
ACS Applied Nano Materials
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2026
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IF 5.8
Lanxiang Wu,Wenlu Mo,Yutang Huang,Xue Zhou,Yuru Zhang,Chunjie Wen
Osimertinib (Osi) is a standard treatment for EGFR mutant NSCLC, but its efficacy is limited by poor bioavailability and adverse effects. To address these limitations, we developed a biomimetic nanoplatform, HM/HMPB@Osi, by encapsulating osimertinib within hollow mesoporous Prussian blue (HMPB) and coating them with a hybrid membrane derived from red blood cells and H1975 lung cancer cells. The Prussian blue core provided strong near-infrared absorption and a high photothermal conversion efficiency (η = 38.76%), enabling effective photothermal therapy. In vitro, HM/HMPB@Osi NPs exhibited selective tumor targeting, cellular uptake, and synergistic reactive oxygen species generation under laser irradiation, leading to enhanced cytotoxicity in NSCLC cells. In vivo, it achieved enhanced tumor accumulation, robust photothermal performance, and remarkable antitumor efficacy with minimal organ toxicity. Collectively, this study demonstrates that the HM/HMPB@Osi platform represents a promising photothermal/targeted therapy strategy for overcoming the limitations of osimertinib monotherapy in NSCLC.
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高影响因子
APPLIED SURFACE SCIENCE
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2024
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IF 6.3
Tao Xu,Huan Liu,Jing Tang,Wenxi Wen,Chenjie Gu,Tao Jiang,Hongbin Xu
Surface enhanced Raman scattering (SERS) with high detection sensitivity has emerged as a fascinating protocol for monitoring trace amount of drugs in clinical serum sample. Herein, a simple and environmentally friendly photo-induced in-situ reduction strategy was proposed to synthesize RP@Ag composites with both SERS and photocatalytic activities. By carefully adjusting the concentration of the Ag source in the precursor solution, the amount and diameter of the decorated Ag nanoparticles were precisely tuned. The resulting optimal RP@Ag composites exhibited reliable SERS enhancement ability (enhancement factor: 1.76 × 10 7 ) and the highest degradation efficiency (degradation ratio: 95.04 %, irradiation time: 120 mins) in recyclable detection of Rhodamine B. After further confirming the reliable accuracy, sensitivity, homogeneity, and durability of the RP@Ag composites, they were used to monitor osimertinib and enabled an extremely low limit of detection as 1.63 × 10 −7 mg/mL. In particular, such a recyclable SERS platform achieved perfect recovery rates, the obtained deviations were all within 10 % in the monitoring of clinical samples from patients taking medicine for different durations.
研究领域:
分析化学
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药物分析
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材料科学
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高影响因子
JOURNAL OF CHROMATOGRAPHY A
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2023
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IF 4.1
Yehong Han,Mingyu Wang,Chunliu Yang,Zihui Zhao,Yanan Yuan,Hongyuan Yan
Osimertinib (OSIM) is widely used as a mainstream drug for the treatment of non-small cell lung cancer (NSCLC). However, the lack of a rapid extraction and detection method for OSIM and its metabolite, AZ-5104, has limited clinical drug metabolism and drug resistance research because the drug is unstable. In this study, a new ionic liquid hybrid hierarchical porous material (IL-HHPM) was synthesized with hierarchical porous structures, including micropores (1.6–2.0 nm), mesopores (2.0–50.0 nm), macropores (50.0–148.7 nm), and multiple functional groups via a one-step hydrothermal method using silanized ionic liquids (IL) as functionalized hybrid monomer. The IL-HHPM has the advantages of a high specific surface area (437.4 ± 4.6 m 2 g −1 ), sizable pore volume (0.74 cm 3 g −1 ), and fast mass transfer, additionally, the IL-HHPM adsorbed OSIM and AZ-5104 via π-π interactions and hydrogen bonding. OSIM and AZ-5104 were rapidly extracted and measured in human urine using rapid and miniaturized centrifugal spin-column extraction (MCSCE), which was based on the IL-HHPM. The optimized factors for the extraction recoveries of OSIM and AZ-5104 were adsorbent dosage (8.0 mg), sample volume (0.5 mL), and operation time (9.0 min), and markedly reduced the adsorbent dosage and operation time. The IL-HHPM-MCSCE-HPLC method displayed good linearity (0.02−5.00 μg mL −1 , r ≥ 0.9997), satisfying accuracy (spiked recoveries of 87.7%−100.0%), and good precision (RSDs ≤ 7.0%). The developed method is rapid, sensitive, and reproducible for the simultaneous determination of trace level of OSIM and AZ-5104 in human urine.
研究领域:
分析化学
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药理学
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临床医学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING SCIENCE
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2024
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IF 4.1
Xiaoxiao Liang,Yanru Wu,Yuehua Deng,Xingye Zeng,Shufeng Shan,Yanbin Jiang,Huaiyu Yang
Multi-component crystal based on supramolecular self-assembly is an effective strategy to modify the physicochemical properties of poorly water-soluble drugs. In this study, eight novel multi-component crystals of Osimertinib (AZD) were firstly synthesized under the guidance of theoretical analysis. Five single crystals were successfully obtained, and the AZD-FMS cocrystal shows a distinctive structure wherein free FMS filled in the skeleton, which may be crucial for maintaining morphology. Analysis of crystal structures and Hirshfeld surfaces indicated the involvement of N−H···O and N···H−O hydrogen bonds in the multi-component crystals. Owing to robust intermolecular interactions, multi-component crystals exhibited improved solubility/dissolution rate compared to pure AZD. Multivariate analysis revealed coformers and strong solute–solvent interactions determined the solubility/dissolution rate. Multi-component crystals showed superior stability in solution and low humidity. Moreover, AZD-FSM increased 5.2-fold anti-tumor activity over AZD, which is anticipated to enhance efficacy, reduce drug toxicity, combat drug resistance, and transform from laboratory to clinical application.
研究领域:
药物化学
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材料科学
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癌症研究
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高影响因子
危险品化学品经营许可证（带存储）