Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the ‘reversed’ amide scaffold

详细信息    查看全文

• 作者：Zhixiang Xu^a ; ^&dagger ; ; Xiangxiang Xu^a ; ^&dagger ; ; Ruadhan O&rsquo ; Laoi^b ; Haikuo Ma^a ; Jiyue Zheng^a ; ^{jyzheng@suda.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Shuaishuai Chen^c ; Lusong Luo^c ; ^{lusong.luo@beigene.com" class="auth_mail" title="E-mail the corresponding author} ; Zhilin Hu^d ; Sudan He^d ; Jiajun Li^a ; Hongjian Zhang^a ; Xiaohu Zhang^a ; ^{xiaohuzhang@suda.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BPO ; benzoyl peroxide ; DCM ; dichloromethane ; DIPEA ; N ; N-diisopropylethylamine ; DMF ; N ; N-dimethylformamide ; DMSO ; dimethyl sulfoxide ; FaSSIF ; fasted state simulated intestinal fluid ; HATU ; 1-[bis(dimethylamino)methylene]-1H-1 ; 2 ; 3-triazolo[4 ; 5-b]pyridinium 3-oxid hexafluorophosphate ; SEM ; standard error measurement ; SGF ; simulated gastric fluid ; STF ; super-top flash ; TFA ; trifluoroacetic acid
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：24
• 期：22
• 页码：5861-5872
• 全文大小：4771 K

文摘

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.