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Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c] pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer

文献类型：期刊论文

作者Li, Yang4,6; Fang, Yan3,5; Chen, Xiaoyu4,6; Tong, Linjiang5; Feng, Fang5; Zhou, Qianqian1,3,5; Chen, Shulun5,6; Ding, Jian1,3,5; Xie, Hua1,2,3,5; Zhang, Ao4,6
刊名ACTA PHARMACEUTICA SINICA B
出版日期2025
卷号15期号:1页码:438-466
关键词P21-activated kinase 4 Tetrahydrobenzofuro[2 3-c]pyridine Structure-activity relationship Allosteric inhibitor Pharmacokinetics properties Kinase selectivity Pancreatic cancer Immune infiltration
ISSN号2211-3835
DOI10.1016/j.apsb.2024.10.002
英文摘要The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC50 values of 0.38 and 0.50 mmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration. @ 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词PAK4 ; KPT-9274 ; PROTEIN ; POTENT ; NAMPT
资助项目China National Innovation of Science and Technology[2021ZD0204004] ; National Natural Science Foundation of China[82273767] ; National Natural Science Foundation of China[82073073] ; National Natural Science Foundation of China[82122045] ; National Natural Science Foundation of China[82273948] ; Major Projects for Shanghai Zhang jiang National Independent Innovation of China[ZJ2021-ZD-007] ; Innovative research team of high-level local universities in Shanghai (China)[SHSMU-ZDCX20210802] ; Project of Shanghai Institute of Materia Medica, CAS (China)[SIMM0120231001] ; High-level Innovative Research Institute, Department of Science and Technology of Guangdong Province (China)[2021B0909050003]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001427047000001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/316314]  
专题新药研究国家重点实验室
通讯作者Xie, Hua; Zhang, Ao
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Shanghai Jiao Tong Univ, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Li, Yang,Fang, Yan,Chen, Xiaoyu,et al. Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c] pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer[J]. ACTA PHARMACEUTICA SINICA B,2025,15(1):438-466.
APA Li, Yang.,Fang, Yan.,Chen, Xiaoyu.,Tong, Linjiang.,Feng, Fang.,...&Zhang, Ao.(2025).Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c] pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer.ACTA PHARMACEUTICA SINICA B,15(1),438-466.
MLA Li, Yang,et al."Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-c] pyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer".ACTA PHARMACEUTICA SINICA B 15.1(2025):438-466.

入库方式： OAI收割

来源：上海药物研究所

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