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| 1 | Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors显示文摘Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy.In this study,we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives.Kinase inhibition,cell proliferation,and whole blood stability assays were used to evaluate their activity on FGFR,allowing us to explore structureàactivity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’selectivity and reactivity.Among them,compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation,and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis.Moreover,10h displayed highly potent antitumor efficacy (TGI Z 91.6%,at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model. | Xiaowei Wu Mengdi Dai Rongrong Cui Yulan Wang Chunpu Li Xia Peng Jihui Zhao Bao Wang Yang Dai Dan Feng Tianbiao Yang Hualiang Jiang Meiyu Geng Jing Ai Mingyue Zheng Hong Liu | 2021 | Acta Pharmaceutica Sinica B2021，11，3： | 0 |
| 2 | Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors显示文摘a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development. | Feifei Fang Yang Dai Hao Wang Yinchun Ji Xuewu Liang Xia Peng Jiyuan Li Yangrong Zhao Chunpu Li Danyi Wangh Yazhou Li Dong Zhang Dan Zhang Meiyu Geng Hong Liu Jing Ai Yu Zhou | 2023 | Acta Pharmaceutica Sinica B2023，13，12： | 0 |
| 3 | Optimal Culture Capacity of White Shrimp (Litopenaeus vannamei) and Razor Clam (Sinonovacula constricta) in a New Series-Connection Culture Model显示文摘To construct an effective circular mix-culture model and investigate its culture capacity,we established one small and one large systems,with white shrimp(Litopenaeus vannamei)and razor clam(Sinonovacula constricta)cultured in separate ponds.The culture water from the L.vannamei was pumped to the S.constricta,and the culture water from the S.constricta overflowed back into the L.vannamei via gravity.In trial I,we tested four culture densities(groups 1–4),and monitored water quality,growth indices,and digestive and immune enzyme activities.From the results,the nitrogen and phosphorus levels generally increased then declined after 56 days,and were lower in groups 1 and 2.The specific growth rate of group 2 was the highest.After 56 days,activities of four digestive enzymes were increased in group 2,and lysozyme activity was significantly decreased in S.constricta in groups 1–4;Alkaline phosphatase activity of L.vannamei was increased in group 3,but decreased in S.constricta in groups 2–4;Acid phosphatase activity was significantly higher in groups 1–3(P<0.05),while SOD and CAT activities were significantly elevated in group 2(P<0.05).Thus,we applied group 2 density for trial II.In trial II,nitrogen and phosphorus concentrations declined significantly during the latter stages,and growth indices were higher than the control(P<0.05).The yields of L.vannamei and S.constricta were significantly higher than the control(P<0.05).The results revealed a good circular mix-culture system with the optimal culture capacity for L.vannamei(40 ind m^(−2))and S.constricta(300 ind m^(−2)),which provided a reference for the future culture of them. | HU Jiabao ZHAO Chunpu BAO Gege LUO Yunhui WANG Danli XU Jilin XU Shanliang | 2022 | Journal of Ocean University of China2022，21，6： | 0 |
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