Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro2,3-cpyridine derivatives as p21-activated kinase 4 inhibitors for treatment of pancreatic cancer.
10.1016/j.apsb.2024.10.002
- Author:
Yang LI
1
;
Yan FANG
2
;
Xiaoyu CHEN
1
;
Linjiang TONG
2
;
Fang FENG
2
;
Qianqian ZHOU
2
;
Shulun CHEN
1
;
Jian DING
2
;
Hua XIE
2
;
Ao ZHANG
1
Author Information
1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
- Publication Type:Journal Article
- Keywords:
Allosteric inhibitor;
Immune infiltration;
Kinase selectivity;
P21-activated kinase 4;
Pancreatic cancer;
Pharmacokinetics properties;
Structure-activity relationship;
Tetrahydrobenzofuro[2,3-c]pyridine
- From:
Acta Pharmaceutica Sinica B
2025;15(1):438-466
- CountryChina
- Language:English
-
Abstract:
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 μmol/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.
