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Discovery of a natural small‑molecule AMP‑activated kinase activator that alleviates nonalcoholic steatohepatitis

marine Life Science & Technology 2023年第2期5卷 196-210页

作者： Jin Chen Li Xu Xue-Qing Zhang Xue Liu Zi-Xuan Zhang Qiu-Mei Zhu Jian-Yu Liu Muhammad Omer Iqbal Ning Ding Chang-Lun Shao Mei-Yan Wei Yu-Chao Gu Key Laboratory of marine drugs the Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China Laboratory for marine drugs and Bioproducts Laoshan LaboratoryQingdao 266237China College of Food Science and Engineering Ocean University of ChinaQingdao 266003China Key Laboratory of Glycoscience and Glycotechnology of Shandong Province Qingdao 266003China The Massachusetts General Hospital Cancer Center Harvard Medical SchoolBostonMA 02114USA

Non-alcoholic steatohepatitis(NASH)is a primary cause of cirrhosis and hepatocellular carcinoma.Unfortunately,there is no approved drug treatment for NASH.AMP-activated kinase(AMPK)is an important metabolic sensor and whole-body regulator.It has been proposed that AMPK activators could be used for treating metabolic diseases such as obesity,type 2 diabetes and NASH.In this study,we screened a marine natural compound library by monitoring AMPK activity and found a potent AMPK activator,candidusin A(CHNQD-0803).Further studies showed that CHNQD-0803 directly binds recombinant AMPK with a K_(D) value of 4.728×10^(-8) M and activates AMPK at both molecular and intracellular levels.We then investigated the roles and mechanisms of CHNQD-0803 in PA-induced fat deposition,LPS-stimulated infammation,TGF-β-induced fbrosis cell models and the MCD-induced mouse model of NASH.The results showed that CHNQD-0803 inhibited the expression of adipogenesis genes and reduced fat deposition,negatively regulated the NF-κB-TNFαinfammatory axis to suppress infammation,and ameliorated liver injury and fbrosis.These data indicate that CHNQD-0803 as an AMPK activator is a novel potential therapeutic candidate for NASH treatment.

关键词： NASH AMPK Infammation Lipid metabolism Fibrosis marine drug

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Plinabulin:A marine drug Candidate for Anti-tumor

Plinabulin:A Marine Drug Candidate for Anti-tumor

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第十二届海洋药物学术年会

作者： SUN Tian-wen WANG Shi-xiao ZHAO Jian-chun DING Zhong-peng CHENG He-juan LIU Xiao-chun LIU Li CAI Bing GUAN Hua-shi LI Wen-bao School of Medicine and Pharmacy Ocean University of China marine Biomedical Research Institute of Qingdao

Plinabulin is a synthesized diketopiperazine type tubulin inhibitor discovered based on the structure-activity relationship（SAR）study of Phenylahistin,which was isolated from Aspergillus.It was observed that Plinabulin binds between alpha and beta tubulin subunit which is close to colchicine-binding site of tubuhn.Further study indicated that it has good efficacy,pharmacokinetics and safety properties,current it is in phaseⅢclinical study.Now,we are working on optimization of its synthesis process.With ethyl isocyanoacetate and three methyl acetic anhydride as starting materials,the imidazole aldehyde was obtained through four steps;and then the target molecule was accomplished through two steps of condensation reaction,the total synthesis yield is 12%.The double bond Z,E isomers can be produced in the second condensation reaction,and the Z isomer,which has anti-tumor activity,can be obtained by avoiding light.Bioactivity screening indicated that Plinabulin has strong inhibition the growth of A431 human skin cancer cell,the inhibition rate was91.8%in 12.5 nm concentration conditions.The intracellular fluorescence intensity of the microtubule protein enhanced,and the cell morphology altered were observed with using Alexa488 staining.In order to obtain a new generation of anti-tumor drugs with better biological activity and to overcome the existing drug resistance,our group has designed and synthesized a series of novel derivatives based on the structure of Plinabulin.MBRI-001,a new marine anti-tumor drug candidate having good druggability,was selected to preclinical study through activity screening,preliminary pharmacokinetics and safety studies.

关键词： Plinabulin Tubulin inhibitor marine drug Anti-tumor drug candidate

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