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RISS 인기검색어
- 검색키워드
- 저자 : Jianming Guo (검색결과 3 건)
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Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors
Zhang, Jianming,Adriá,n, Francisco J.,Jahnke, Wolfgang,Cowan-Jacob, Sandra W.,Li, Allen G.,Iacob, Roxana E.,Sim, Taebo,Powers, John,Dierks, Christine,Sun, Fangxian,Guo, Gui-Rong,Ding, Qiang,Okra Macmillan Publishers Limited. All rights reserved 2010 Nature Vol.463 No.7280
In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
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Shu Jiang,Jing Yang,Dawei Qian,Jianming Guo,Er-xin Shang,Jin-ao Duan,Jun Xu 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.2
Ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS)technique combined with MetabolynxTM software was usedfor analysis of the metabolites of quercitrin by the isolatedhuman intestinal bacteria from the human feces. Four metabolitesof quercitrin were detected and tentatively identifiedbased on the characteristics of their protonated ions. Themetabolites were metabolized by four main metabolic pathwaysincluding hydroxylation, demethylation, deglycosylationand ring-cleavage. Quercitrin was metabolized to the hydroxyquercitrinand desmethylquercitrin by themajority of theisolated intestinal bacteria such as Bacteroides sp. 54, and wasdegraded to the deglycosylated product quercetin by rhamnosidaseand further ring-cleavage metabolite 3,4-dihydroxybenzoicacid by the minority of the isolated bacteria such asBacteroides sp. 45. The metabolic pathways and most of themetabolites of quercitrin were reported for the first time.
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Xianglai Xu,Ying Wang,Zhaoyi Chen,Yanjun Zhu,Jiajun Wang,Jianming Guo 대한암학회 2023 Cancer Research and Treatment Vol.55 No.4
Purpose Immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) has become the first-line treatment for advanced renal cell carcinoma, despite the lack of prognostic biomarkers. Cyclin-dependent kinase 5 (CDK5) affects the tumor microenvironment, which may influence the efficacy of TKI+IO. Materials and Methods Two cohorts from our center (Zhongshan Metastatic Renal Cell Carcinoma [ZS-MRCC] cohort, Zhongshan High-risk Localized Renal Cell Carcinoma [ZS-HRRCC] cohort) and one cohort from a clinical trial (JAVELIN-101) were enrolled. The expression of CDK5 of each sample was determined by RNA sequencing. Immune infiltration and T cell function were evaluated by flow cytometry and immunohistochemistry. Response and progression-free survival (PFS) were set as primary endpoints. Results Patients of low CDK5 expression showed higher objective response rate (60.0% vs. 23.3%) and longer PFS in both cohorts (ZS-MRCC cohort, p=0.014; JAVELIN-101 cohort, p=0.040). CDK5 expression was enhanced in non-responders (p < 0.05). In the ZS-HRRCC cohort, CDK5 was associated with decreased tumor-infiltrating CD8+ T cells, which was proved by immunohistochemistry (p < 0.05) and flow cytometry (Spearman’s ρ=–0.49, p < 0.001). In the high CDK5 subgroup, CD8+ T cells revealed a dysfunction phenotype with decreased granzyme B, and more regulatory T cells were identified. A predictive score was further constructed by random forest, involving CDK5 and T cell exhaustion features. The RFscore was also validated in both cohorts. By utilizing the model, more patients might be distinguished from the overall cohort. Additionally, only in the low RFscore did TKI+IO outperform TKI monotherapy. Conclusion High-CDK5 expression was associated with immunosuppression and TKI+IO resistance. RFscore based on CDK5 may be utilized as a biomarker to determine the optimal treatment strategy.
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