Bioorganic and Medicinal Chemistry p. 5861 - 5872 (2016)
Update date:2022-07-30
Topics:
Xu, Zhixiang
Xu, Xiangxiang
O'Laoi, Ruadhan
Ma, Haikuo
Zheng, Jiyue
Chen, Shuaishuai
Luo, Lusong
Hu, Zhilin
He, Sudan
Li, Jiajun
Zhang, Hongjian
Zhang, Xiaohu
The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure–activity-relationship of the novel porcupine inhibitors based on a ‘reversed’ amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a porcupine inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better porcupine inhibitors will be subsequently undertaken and reported in due course.
View MoreContact:+86-574- 87178138; 87297407
Address:No. 809, Liudingxingzuo, cangsong road, Ningbo, China
Anhui Biochem United Pharmaceutical Co., Ltd.
Contact:0086 551 5167062 / 5228268
Address:No. 30 Hongfeng Road, Hi-Tech Development Zone, Hefei (230088), China
SHIJIAZHUANG CHENSHI IMPORT AND EXPORT CO.,LTD
Contact:+86-311-89871056
Address:RM2017 BUILDING CTIANSHAN GALAXY PLAZA,NO168 CHANGJIANG ROAD,GAOXIN DISTRICT,SHIJIAZHUANG CITY, HEBEI,CHINA
Nantong Advance Chemical Co., Ltd
Contact:86-13818730908
Address:Fine Chemical Industry Garden,Beixin Town,Qidong
Ji'an Hairui Natural Plant Co. Ltd.
Contact:0796-8105528
Address:Meilin industry park, Qingyuan district Ji'an City, Jiangxi Province
Doi:10.1021/jm000371q
(2000)Doi:10.1007/BF00479572
()Doi:10.1080/10587250108023698
(2001)Doi:10.1016/S0040-4039(00)95178-5
(1989)Doi:10.1016/S0040-4020(01)90874-9
(1971)Doi:10.1002/hlca.19520350634
(1952)